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Volume 41
Issue 1
1 January 2020

ARTICLE CONTENTS

* Table of contents
* Tables of Recommendations
* List of tables
* List of figures
* List of boxes
* Abbreviations and acronyms
* 1 Preamble
* 2 Introduction
* 3 What is cardiovascular disease prevention?
* 4 Total cardiovascular risk
* 5 Lipids and lipoproteins
* 6 Treatment targets and goals
* 7 Lifestyle modifications to improve the plasma lipid profile
* 8 Drugs for treatment of dyslipidaemias
* 9 Management of dyslipidaemias in different clinical settings
* 10 Inflammation
* 11 Monitoring of lipids and enzymes in patients on lipid-lowering therapy
* 12 Cost-effectiveness of cardiovascular disease prevention by lipid
modification
* 13 Strategies to encourage adoption of healthy lifestyle changes and
adherence to lipid-modifying therapies
* 14 Key messages
* 15 Gaps in the evidence
* 16 ‘What to do’ and ‘what not to do’ messages from the Guidelines
* 17 Supplementary data
* 18 Appendix
* 19 References
* Author notes
* Supplementary data

* < Previous
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Journal Article

2019 ESC/EAS GUIDELINES FOR THE MANAGEMENT OF DYSLIPIDAEMIAS: LIPID MODIFICATION
TO REDUCE CARDIOVASCULAR RISK: THE TASK FORCE FOR THE MANAGEMENT OF
DYSLIPIDAEMIAS OF THE EUROPEAN SOCIETY OF CARDIOLOGY (ESC) AND EUROPEAN
ATHEROSCLEROSIS SOCIETY (EAS)

François Mach,
François Mach
Chairperson Switzerland
Corresponding authors: François Mach, Cardiology Department, Geneva University
Hospital, 4 Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland. Tel: +41 223 727
192, Fax: +41 223 727 229, Email: francois.mach@hcuge.ch. Colin Baigent,
Nuffield Department of Population Health, University of Oxford, Richard Doll
Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. Tel: +44 1865 743
741, Fax: +44 1865 743 985, Email: colin.baigent@ndph.ox.ac.uk. Alberico L.
Catapano, Department of Pharmacological and Biomolecular Sciences, University of
Milan, Via Balzaretti, 9, 20133 Milan, and Multimedica IRCCS, Milan, Italy. Tel:
+39 02 5031 8401, Fax: +39 02 5031 8386, Email: alberico.catapano@unimi.it.
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Colin Baigent,
Colin Baigent
Chairperson United Kingdom
Corresponding authors: François Mach, Cardiology Department, Geneva University
Hospital, 4 Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland. Tel: +41 223 727
192, Fax: +41 223 727 229, Email: francois.mach@hcuge.ch. Colin Baigent,
Nuffield Department of Population Health, University of Oxford, Richard Doll
Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. Tel: +44 1865 743
741, Fax: +44 1865 743 985, Email: colin.baigent@ndph.ox.ac.uk. Alberico L.
Catapano, Department of Pharmacological and Biomolecular Sciences, University of
Milan, Via Balzaretti, 9, 20133 Milan, and Multimedica IRCCS, Milan, Italy. Tel:
+39 02 5031 8401, Fax: +39 02 5031 8386, Email: alberico.catapano@unimi.it.
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Alberico L Catapano,
Alberico L Catapano
Chairperson Italy
Corresponding authors: François Mach, Cardiology Department, Geneva University
Hospital, 4 Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland. Tel: +41 223 727
192, Fax: +41 223 727 229, Email: francois.mach@hcuge.ch. Colin Baigent,
Nuffield Department of Population Health, University of Oxford, Richard Doll
Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. Tel: +44 1865 743
741, Fax: +44 1865 743 985, Email: colin.baigent@ndph.ox.ac.uk. Alberico L.
Catapano, Department of Pharmacological and Biomolecular Sciences, University of
Milan, Via Balzaretti, 9, 20133 Milan, and Multimedica IRCCS, Milan, Italy. Tel:
+39 02 5031 8401, Fax: +39 02 5031 8386, Email: alberico.catapano@unimi.it.
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Konstantinos C Koskinas,
Konstantinos C Koskinas
Switzerland
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Manuela Casula,
Manuela Casula
Italy
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Lina Badimon,
Lina Badimon
Spain
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M John Chapman,
M John Chapman
France
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Guy G De Backer,
Guy G De Backer
Belgium
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Victoria Delgado,
Victoria Delgado
Netherlands
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Brian A Ference,
Brian A Ference
United Kingdom
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Ian M Graham,
Ian M Graham
Ireland
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Alison Halliday,
Alison Halliday
United Kingdom
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Ulf Landmesser,
Ulf Landmesser
Germany
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Borislava Mihaylova,
Borislava Mihaylova
United Kingdom
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Terje R Pedersen,
Terje R Pedersen
Norway
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Gabriele Riccardi,
Gabriele Riccardi
Italy
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Dimitrios J Richter,
Dimitrios J Richter
Greece
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Marc S Sabatine,
Marc S Sabatine
United States of America
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Marja-Riitta Taskinen,
Marja-Riitta Taskinen
Finland
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Lale Tokgozoglu,
Lale Tokgozoglu
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Olov Wiklund,
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ESC Scientific Document Group
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François Mach, Colin Baigent and Alberico L. Catapano chairpersons contributed
equally to the document.

Alberico L. Catapano, Manuela Casula, Gabriele Riccardi, Marja-Riitta Taskinen,
Lale Tokgozoglu, Olov Wiklund, Alberto Corsini, Meral Kayikcioglu, Philippe
Moulin, Xavier Pintó, Kausik K. Ray, Željko Reiner, Erik Stroes, Alexandros D.
Tselepis, Margus Viigimaa and Michal Vrablik: representing the EAS.

Author Notes
European Heart Journal, Volume 41, Issue 1, 1 January 2020, Pages 111–188,
https://doi.org/10.1093/eurheartj/ehz455
Published:
31 August 2019
A correction has been published: European Heart Journal, Volume 41, Issue 44, 21
November 2020, Page 4255, https://doi.org/10.1093/eurheartj/ehz826
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* Article contents
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* Cite

CITE

François Mach, Colin Baigent, Alberico L Catapano, Konstantinos C Koskinas,
Manuela Casula, Lina Badimon, M John Chapman, Guy G De Backer, Victoria
Delgado, Brian A Ference, Ian M Graham, Alison Halliday, Ulf Landmesser,
Borislava Mihaylova, Terje R Pedersen, Gabriele Riccardi, Dimitrios J
Richter, Marc S Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov
Wiklund, ESC Scientific Document Group, 2019 ESC/EAS Guidelines for the
management of dyslipidaemias: lipid modification to reduce cardiovascular
risk: The Task Force for the management of dyslipidaemias of the European
Society of Cardiology (ESC) and European Atherosclerosis Society (EAS),
European Heart Journal, Volume 41, Issue 1, 1 January 2020, Pages 111–188,
https://doi.org/10.1093/eurheartj/ehz455

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Guidelines, dyslipidaemias, cholesterol, triglycerides, low-density
lipoproteins, high-density lipoproteins, apolipoprotein B, lipoprotein(a),
lipoprotein remnants, total cardiovascular risk, treatment (lifestyle),
treatment (drugs), treatment (adherence), very low-density lipoproteins,
familial hypercholesterolaemia
Topic:
* atherosclerosis
* dyslipidemias
* ldl cholesterol lipoproteins
* high density lipoprotein cholesterol
* triglycerides
* statins
* lipoproteins
* cardiovascular diseases
* heart disease risk factors
* cholesterol
* apolipoproteins b
* plasma
* guidelines
* lipids
* mortality

Issue Section:
ESC/EAS GUIDELINES

For the Supplementary Data which include background information and detailed
discussion of the data that have provided the basis for the Guidelines see
https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz455#supplementary-data

TABLE OF CONTENTS

* Abbreviations and acronyms 114

* 1 Preamble 116

* 2 Introduction 118

* 2.1 What is new in the 2019 Guidelines? 118

* 3 What is cardiovascular disease prevention? 118

* 3.1 Definition and rationale 118

* 3.2 Development of the Joint Task Force Guidelines for the management of
dyslipidaemias 118

* 4 Total cardiovascular risk 118

* 4.1 Total cardiovascular risk estimation 118

* 4.1.1 Rationale for assessing total cardiovascular disease risk 121

* 4.1.2 How to use the risk estimation charts 124

* 4.2 Risk levels 125

* 4.2.1 Role of non-invasive cardiovascular imaging techniques in the
assessment of total cardiovascular disease risk 126

* 4.2.2 Risk-based intervention strategies 127

* 5 Lipids and lipoproteins 127

* 5.1 Biological role of lipids and lipoproteins 127

* 5.2 Role of lipids and lipoproteins in the pathophysiology of
atherosclerosis 127

* 5.3 Evidence for the causal effects of lipids and lipoproteins on the risk
of atherosclerotic cardiovascular disease 128

* 5.3.1 Low-density lipoprotein cholesterol and risk of atherosclerosis 128

* 5.3.2 Triglyceride-rich lipoproteins and risk of atherosclerosis 128

* 5.3.3 High-density lipoprotein cholesterol and risk of atherosclerosis 129

* 5.3.4 Lipoprotein(a) and risk of atherosclerosis 129

* 5.4 Laboratory measurement of lipids and lipoproteins 129

* 5.4.1 Lipoprotein measurement 129

* 5.4.2 Lipid measurements 20

* 5.4.3 Fasting or non-fasting? 130

* 5.5 Recommendations for measuring lipids and lipoproteins to estimate risk
of atherosclerotic cardiovascular disease 130

* 6 Treatment targets and goals 131

* 7 Lifestyle modifications to improve the plasma lipid profile 132

* 7.1 Influence of lifestyle on total cholesterol and low-density lipoprotein
cholesterol levels 134

* 7.2 Influence of lifestyle on triglyceride levels 134

* 7.3 Influence of lifestyle on high-density lipoprotein cholesterol
levels 135

* 7.4 Lifestyle recommendations to improve the plasma lipid profile 135

* 7.4.1 Body weight and physical activity 135

* 7.4.2 Dietary fat 135

* 7.4.3 Dietary carbohydrate and fibre 136

* 7.4.4 Alcohol 136

* 7.4.5 Smoking 136

* 7.5 Dietary supplements and functional foods for the treatment of
dyslipidaemias 136

* 7.5.1 Phytosterols 136

* 7.5.2 Monacolin and red yeast rice 136

* 7.5.3 Dietary fibre 137

* 7.5.4 Soy 137

* 7.5.5 Policosanol and berberine 27

* 7.5.6 n-3 unsaturated fatty acids 137

* 8 Drugs for treatment of dyslipidaemias 137

* 8.1 Statins 137

* 8.1.1 Mechanism of action 137

* 8.1.2 Effects on lipids 137

* 8.1.2.1 Low-density lipoprotein cholesterol 137

* 8.1.2.2 Triglycerides 137

* 8.1.2.3 High-density lipoprotein cholesterol 137

* 8.1.2.4 Lipoprotein(a) 137

* 8.1.3 Other effects of statins 138

* 8.1.3.1 Effect on cardiovascular morbidity and mortality 138

* 8.1.4 Adverse effects and interactions of statins 138

* 8.1.4.1 Adverse effects on muscle 138

* 8.1.4.2 Adverse effects on the liver 139

* 8.1.4.3 Increased risk of new-onset diabetes mellitus 139

* 8.1.4.4 Increased risk of haemorrhagic stroke 139

* 8.1.4.5 Adverse effects on kidney function 139

* 8.1.4.6 Interactions 139

* 8.2 Cholesterol absorption inhibitors 140

* 8.2.1 Mechanism of action 140

* 8.2.2 Effects on lipids 140

* 8.2.3 Effect on cardiovascular morbidity and mortality 140

* 8.2.4 Adverse effects and interactions 140

* 8.3 Bile acid sequestrants 140

* 8.3.1 Mechanism of action 140

* 8.3.2 Effects on lipids 140

* 8.3.3 Effect on cardiovascular morbidity and mortality 140

* 8.3.4 Adverse effects and interactions 141

* 8.4 Proprotein convertase subtilisin/kexin type 9 inhibitors 141

* 8.4.1 Mechanism of action 141

* 8.4.2 Effects on lipids 141

* 8.4.2.1 Low-density lipoprotein cholesterol 141

* 8.4.2.2 Triglycerides and high-density lipoprotein cholesterol 141

* 8.4.2.3 Lipoprotein(a) 141

* 8.4.3 Effect on cardiovascular morbidity and mortality 141

* 8.4.4 Adverse effects and interactions 142

* 8.5 Lomitapide 142

* 8.6 Mipomersen 142

* 8.7 Fibrates 142

* 8.7.1 Mechanism of action 142

* 8.7.2 Effects on lipids 142

* 8.7.3 Effect on cardiovascular morbidity and mortality 143

* 8.7.4 Adverse effects and interactions 143

* 8.8 n-3 fatty acids 143

* 8.8.1 Mechanism of action 143

* 8.8.2 Effects on lipids 143

* 8.8.3 Effect on cardiovascular morbidity and mortality 143

* 8.8.4 Safety and interactions 144

* 8.9 Nicotinic acid 144

* 8.10 Cholesteryl ester transfer protein inhibitors 144

* 8.11 Future perspectives 144

* 8.11.1 New approaches to reduce low-density lipoprotein cholesterol 144

* 8.11.2 New approaches to reduce triglyceride-rich lipoproteins and their
remnants 144

* 8.11.3 New approaches to increase high-density lipoprotein cholesterol 145

* 8.11.4 New approaches to reduce lipoprotein(a) levels 145

* 8.12 Strategies to control plasma cholesterol 145

* 8.13 Strategies to control plasma triglycerides 145

* 9 Management of dyslipidaemias in different clinical settings 148

* 9.1 Familial dyslipidaemias 148

* 9.1.1 Familial combined hyperlipidaemia 148

* 9.1.2 Familial hypercholesterolaemia 148

* 9.1.2.1 Heterozygous familial hypercholesterolaemia 148

* 9.1.2.2 Homozygous familial hypercholesterolaemia 151

* 9.1.2.3 Familial hypercholesterolaemia in children 151

* 9.1.3 Familial dysbetalipoproteinaemia 151

* 9.1.4 Genetic causes of hypertriglyceridaemia 151

* 9.1.4.1 Action to prevent acute pancreatitis in severe
hypertriglyceridaemia 151

* 9.1.5 Other genetic disorders of lipoprotein metabolism 152

* 9.2 Women 152

* 9.2.1 Effects of statins in primary and secondary prevention 152

* 9.2.2 Non-statin lipid-lowering drugs 152

* 9.2.3 Hormone therapy 152

* 9.3 Older people 152

* 9.3.1 Effects of statins in primary and secondary prevention 153

* 9.3.2 Adverse effects, interactions, and adherence 153

* 9.4 Diabetes and metabolic syndrome 153

* 9.4.1 Specific features of dyslipidaemia in insulin resistance and type 2
diabetes 153

* 9.4.2 Evidence for lipid-lowering therapy 154

* 9.4.2.1 Low-density lipoprotein cholesterol 154

* 9.4.2.1 Triglycerides and high-density lipoprotein cholesterol 154

* 9.4.3 Type 1 diabetes 155

* 9.4.4 Management of dyslipidaemia for pregnant women with diabetes 155

* 9.5 Patients with acute coronary syndromes and patients undergoing
percutaneous coronary intervention 156

* 9.5.1 Lipid-lowering therapy in patients with acute coronary syndromes 156

* 9.5.1.1 Statins 156

* 9.5.1.2 Ezetimibe 156

* 9.5.1.3 Proprotein convertase subtilisin/kexin type 9 inhibitors 156

* 9.5.1.4 n-3 polyunsaturated fatty acids 157

* 9.5.1.5 Cholesteryl ester transfer protein inhibitors 157

* 9.5.2 Lipid-lowering therapy in patients undergoing percutaneous coronary
intervention 157

* 9.6 Stroke 158

* 9.7 Heart failure and valvular diseases 158

* 9.7.1 Prevention of incident heart failure in coronary artery disease
patients 158

* 9.7.2 Chronic heart failure 158

* 9.7.3 Valvular heart diseases 158

* 9.8 Chronic kidney disease 159

* 9.8.1 Lipoprotein profile in chronic kidney disease 159

* 9.8.2 Evidence for risk reduction through statin-based therapy in patients
with chronic kidney disease 159

* 9.8.3 Safety of lipid management in patients with chronic kidney
disease 159

* 9.9 Transplantation 160

* 9.10 Peripheral arterial disease 160

* 9.10.1 Lower extremity arterial disease 160

* 9.10.2 Carotid artery disease 161

* 9.10.3 Retinal vascular disease 161

* 9.10.4 Secondary prevention in patients with abdominal aortic aneurysm 161

* 9.10.5 Renovascular atherosclerosis 161

* 9.11 Other special populations at risk of atherosclerotic cardiovascular
disease 161

* 10 Inflammation 161

* 11 Monitoring of lipids and enzymes in patients on lipid-lowering
therapy 162

* 12 Cost-effectiveness of cardiovascular disease prevention by lipid
modification 162

* 13 Strategies to encourage adoption of healthy lifestyle changes and
adherence to lipid-modifying therapies 166

* 14 Key messages 166

* 15 Gaps in evidence 167

* 16 Evidence-based ‘to do’ and ‘not to do’ messages from the Guidelines 168

* 17 Supplementary data 170

* 18 Appendix 170

* 19 References 171

TABLES OF RECOMMENDATIONS

* Recommendations for cardiovascular imaging for risk assessment of
atherosclerotic cardiovascular disease 127

* Recommendations for cardiovascular disease risk estimation 127

* Recommendations for lipid analyses for cardiovascular disease risk
estimation 131

* Recommendations for treatment goals for low-density lipoprotein
cholesterol 132

* Recommendations for pharmacological low-density lipoprotein cholesterol
lowering 145

* Recommendations for drug treatment of patients with
hypertriglyceridaemia 148

* Recommendations for the detection and treatment of patients with heterozygous
familial hypercholesterolaemia 150

* Recommendations for the treatment of dyslipidaemias in older people (aged >65
years) 153

* Recommendations for the treatment of dyslipidaemias in diabetes mellitus 155

* Recommendations for lipid-lowering therapy in very- high-risk patients with
acute coronary syndromes 157

* Recommendations for lipid-lowering therapy in very-high-risk patients
undergoing percutaneous coronary intervention 157

* Recommendations for lipid-lowering therapy for prevention of atherosclerotic
cardiovascular disease events in patients with prior ischaemic stroke 158

* Recommendations for the treatment of dyslipidaemias in chronic heart failure
or valvular heart diseases 159

* Recommendations for lipid management in patients with moderate to severe
(Kidney Disease Outcomes Quality Initiative stages 3–5) chronic kidney
disease 159

* Recommendations for low-density lipoprotein lowering in solid organ
transplant patients 160

* Recommendations for lipid-lowering drugs in patients with peripheral arterial
disease (including carotid artery disease) 161

LIST OF TABLES

* Table 1 Classes of recommendations 117

* Table 2 Levels of evidence 117

* Table 3 New recommendations, and new and revised concepts 119

* Table 4 Cardiovascular risk categories 125

* Table 5 Intervention strategies as a function of total cardiovascular risk
and untreated low-density lipoprotein cholesterol levels 126

* Table 6 Physical and chemical characteristics of human plasma
lipoproteins 128

* Table 7 Treatment targets and goals for cardiovascular disease
prevention 133

* Table 8 Impact of specific lifestyle changes on lipid levels 134

* Table 9 Food choices to lower low-density lipoprotein cholesterol and improve
the overall lipoprotein profile 135

* Table 10 Drugs potentially interacting with statins metabolized by cytochrome
P450 3A4 leading to increased risk of myopathy and rhabdomyolysis 139

* Table 11 Genetic disorders of lipoprotein metabolism 149

* Table 12 Dutch Lipid Clinic Network diagnostic criteria for familial
hypercholesterolaemia 149

* Table 13 Summary of recommendations for monitoring lipids and enzymes in
patients, before and on lipid-lowering therapy 163

LIST OF FIGURES

* Figure 1 Systematic Coronary Risk Estimation chart for European populations
at high cardiovascular disease risk 122

* Figure 2 Systematic Coronary Risk Estimation chart for European populations
at low cardiovascular disease risk 123

* Figure 3 Expected clinical benefit of low-density lipoprotein
cholesterol-lowering therapies 146

* Figure 4 Treatment goals and algorithm for low-density lipoprotein
cholesterol-lowering according to cardiovascular disease risk 147

* Figure 5 Health impact pyramid 164

* Figure 6 Absolute reductions in major vascular events with statin
therapy 165

LIST OF BOXES

* Box 1 How to use the risk estimation charts 124

* Box 2 Risk estimation charts for different countries 124

* Box 3 Qualifiers 124

* Box 4 Factors modifying Systematic Coronary Risk Estimation risks 124

* Box 5 Risk estimation: key messages 125

* Box 6 Management of dyslipidaemia in women 152

* Box 7 Summary of dyslipidaemia in metabolic syndrome and type 2 diabetes
mellitus 154

* Box 8 Key messages 165

* Box 9 Gaps in the evidence 165

* Box 10 Methods for enhancing adherence to lifestyle changes 166

ABBREVIATIONS AND ACRONYMS

Abbreviations and acronyms
* ABI

Ankle–brachial index

* ACCELERATE

Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein
Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes

* ACCORD

Action to Control Cardiovascular Risk in Diabetes

* ACS

Acute coronary syndrome

* ALT

Alanine aminotransferase

* ANGPTL3

Angiopoietin-like protein 3

* Apo

Apolipoprotein

* ART

Antiretroviral treatment

* ASCEND

A Study of Cardiovascular Events iN Diabetes

* ASCOT-LLA

Anglo-Scandinavian Cardiac Outcomes Trial – Lipid-Lowering Arm

* ASCVD

Atherosclerotic cardiovascular disease

* ASSIGN

CV risk estimation model from the Scottish Intercollegiate Guidelines Network

* AURORA

A study to evaluate the Use of Rosuvastatin in subjects On Regular
haemodialysis: an Assessment of survival and cardiovascular events

* b.i.d.

Twice a day (bis in die)

* BIOSTAT-CHF

BIOlogy Study to TAilored Treatment in Chronic Heart Failure

* BIP

Bezafibrate Infarction Prevention

* BMI

Body mass index

* BP

Blood pressure

* CABG

Coronary artery bypass graft surgery

* CAC

Coronary artery calcium

* CAD

Coronary artery disease

* CANTOS

Canakinumab Antiinflammatory Thrombosis Outcome Study

* CETP

Cholesteryl ester transfer protein

* CHD

Coronary heart disease

* CI

Confidence interval

* CIID

Chronic immune-mediated inflammatory diseases

* CIRT

Cardiovascular Inflammation Reduction Trial

* CK

Creatine kinase

* CKD

Chronic kidney disease

* COM-B

Capability, Opportunity and Motivation

* CORONA

Controlled Rosuvastatin Multinational Trial in Heart Failure

* CPG

Committee for Practice Guidelines

* CT

Computed tomography

* CTT

Cholesterol Treatment Trialists

* CV

Cardiovascular

* CVD

Cardiovascular disease

* CYP

Cytochrome P450

* 4D

Die Deutsche Diabetes Dialyse Studie

* dal-OUTCOMES

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

* DASH

Dietary Approaches to Stop Hypertension

* DGAT-2

Diacylglycerol acyltransferase-2

* DHA

Docosahexaenoic acid

* DM

Diabetes mellitus

* EAPC

European Association of Preventive Cardiology

* EAS

European Atherosclerosis Society

* EBBINGHAUS

Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High
Cardiovascular Risk Subjects

* eGFR

Estimated glomerular filtration rate

* EMA

European Medicines Agency

* EPA

Eicosapentaenoic acid

* ESC

European Society of Cardiology

* EVOLVE

EpanoVa fOr Lowering Very high triglyceridEs

* EVOPACS

EVOlocumab for early reduction of LDL-cholesterol levels in patients with
Acute Coronary Syndromes

* FCH

Familial combined hyperlipidaemia

* FCS

Familial chylomicronaemia syndrome

* FDA

US Food and Drug Administration

* FH

Familial hypercholesterolaemia

* FIELD

Fenofibrate Intervention and Event Lowering in Diabetes

* FOCUS

Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention

* FOURIER

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects
with Elevated Risk

* GFR

Glomerular filtration rate

* GI

Gastrointestinal

* GISSI

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico

* HbA1c

Glycated haemoglobin

* HeFH

Heterozygous familial hypercholesterolaemia

* HDL

High-density lipoprotein

* HDL-C

High-density lipoprotein cholesterol

* HF

Heart failure

* HHS

Helsinki Heart Study

* HIV

Human immunodeficiency virus

* HMG-CoA

Hydroxymethylglutaryl-coenzyme A

* HoFH

Homozygous familial hypercholesterolaemia

* HPS2-THRIVE

Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular
Events

* HR

Hazard ratio

* HTG

Hypertriglyceridaemia

* IDEAL

Incremental Decrease In End-points Through Aggressive Lipid-lowering

* IDL

Intermediate-density lipoproteins

* IL

Interleukin

* ILLUMINATE

Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events

* IMPROVE-IT

Improved Reduction of Outcomes: Vytorin Efficacy International Trial

* IPD

Individual participant data

* JUPITER

Justification for the Use of Statins in Prevention: an Intervention Trial
Evaluating Rosuvastatin

* KDIGO

Kidney Disease: Improving Global Outcomes

* LCAT

Lecithin cholesterol acyltransferase

* LDL

Low-density lipoprotein

* LDL-C

Low-density lipoprotein cholesterol

* LDLR

Low-density lipoprotein receptor

* LEAD

Lower extremity arterial disease

* LEADER

Lower Extremity Arterial Disease Event Reduction

* LPL

Lipoprotein lipase

* Lp(a)

Lipoprotein(a)

* mAb

Monoclonal antibody

* MACE

Major adverse cardiovascular events

* MESA

Multi-Ethnic Study of Atherosclerosis

* MetS

Metabolic syndrome

* MI

Myocardial infarction

* mRNA

Messenger RNA

* MTP

Microsomal triglyceride transfer protein

* NAFLD

Non-alcoholic fatty liver disease

* NNT

Number needed to treat

* NPC1L1

Niemann-Pick C1-like protein 1

* NSTE-ACS

Non-ST elevation acute coronary syndrome

* o.d.

Once a day (omni die)

* ODYSSEY Outcomes

Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During
Treatment With Alirocumab

* PAD

Peripheral arterial disease

* PCI

Percutaneous coronary intervention

* PCSK9

Proprotein convertase subtilisin/kexin type 9

* PPAR-α

Peroxisome proliferator-activated receptor-α

* PREDIMED

Prevención con Dieta Mediterránea

* PROCAM

Prospective Cardiovascular Munster Study

* PROMINENT

Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN
PatiENts With DiabeTes

* PUFA

Polyunsaturated fatty acid

* PURE

Prospective Urban Rural Epidemiology

* RA

Rheumatoid arthritis

* RCT

Randomized controlled trial

* REDUCE-IT

Reduction of Cardiovascular Events with EPA-Intervention Trial

* REVEAL

Randomized EValuation of the Effects of Anacetrapib Through Lipid
modification

* RR

Relative risk

* RYR

Red yeast rice

* SAMS

Statin-associated muscle symptoms

* SBP

Systolic blood pressure

* SCORE

Systematic Coronary Risk Estimation

* SEAS

Simvastatin and Ezetimibe in Aortic Stenosis

* SECURE-PCI

Statins Evaluation in Coronary Procedures and Revascularization

* SFA

Saturated fatty acid

* SHARP

Study of Heart and Renal Protection

* siRNA

Small interfering RNA

* SMI

Severe mental illness

* SPARCL

Stroke Prevention by Aggressive Reduction in Cholesterol Levels

* STAREE

STAtin Therapy for Reducing Events in the Elderly

* STEMI

ST-elevation myocardial infarction

* STRENGTH

Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh
CV Risk PatienTs with Hypertriglyceridemia

* TC

Total cholesterol

* T1DM

Type 1 diabetes mellitus

* T2DM

Type 2 diabetes mellitus

* TGs

Triglycerides

* TIA

Transient ischaemic attack

* TIMI

Thrombolysis In Myocardial Infarction

* TNF

Tumour necrosis factor

* TNT

Treating to New Targets

* TRL

Triglyceride-rich lipoprotein

* ULN

Upper limit of normal

* VA-HIT

Veterans Affairs High Density Lipoprotein Intervention Trial

* VITAL

VITamin D and OmegA-3 Trial

* VLDL

Very low-density lipoprotein

* WHO

World Health Organization

* WOSCOPS

West of Scotland Coronary Prevention Study

1 PREAMBLE

Guidelines summarize and evaluate available evidence with the aim of assisting
health professionals in proposing the best management strategies for an
individual patient with a given condition. Guidelines and their recommendations
should facilitate decision making of health professionals in their daily
practice. However, the final decisions concerning an individual patient must be
made by the responsible health professional(s) in consultation with the patient
and caregiver as appropriate.

A great number of guidelines have been issued in recent years by the European
Society of Cardiology (ESC) and its partners such as European Atherosclerosis
Society (EAS), as well as by other societies and organisations. Because of their
impact on clinical practice, quality criteria for the development of guidelines
have been established in order to make all decisions transparent to the user.
The recommendations for formulating and issuing ESC Guidelines can be found on
the ESC website
(http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines).
The ESC Guidelines represent the official position of the ESC on a given topic
and are regularly updated.

The ESC carries out a number of registries which are essential to assess
diagnostic/therapeutic processes, use of resources and adherence to Guidelines.
These registries aim at providing a better understanding of medical practice in
Europe and around the world, based on data collected during routine clinical
practice.

The guidelines are developed together with derivative educational material
addressing the cultural and professional needs for cardiologists and allied
professionals. Collecting high-quality observational data, at appropriate time
interval following the release of ESC Guidelines, will help evaluate the level
of implementation of the Guidelines, checking in priority the key end points
defined with the ESC Guidelines and Education Committees and Task Force members
in charge.

The Members of this Task Force were selected by the ESC and EAS, including
representation from relevant ESC sub-specialty groups, in order to represent
professionals involved with the medical care of patients with this pathology.
Selected experts in the field from both societies undertook a comprehensive
review of the published evidence for management of a given condition according
to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of
diagnostic and therapeutic procedures was performed, including assessment of the
risk–benefit ratio. The level of evidence and the strength of the recommendation
of particular management options were weighed and graded according to predefined
ESC scales, as outlined in the tables below.

Table 1

Classes of recommendations

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Table 1

Classes of recommendations

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Table 2

Levels of evidence

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Table 2

Levels of evidence

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The experts of the writing and reviewing panels provided declaration of interest
forms for all relationships that might be perceived as real or potential sources
of conflicts of interest. These forms were compiled into one file and can be
found on the ESC website (http://www.escardio.org/guidelines). Any changes in
declarations of interest that arise during the writing period were notified to
the ESC and EAS Chairpersons and updated. The Task Force received its entire
financial support from the ESC and EAS without any involvement from the
healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines. The
Committee is also responsible for the endorsement process of these Guidelines.
The ESC Guidelines undergo extensive review by the CPG and external experts.
After appropriate revisions the Guidelines are approved by all the experts
involved in the Task Force. The finalized document is approved by the CPG and
EAS for publication in the European Heart Journal and Atherosclerosis Journal.
The Guidelines were developed after careful consideration of the scientific and
medical knowledge and the evidence available at the time of their dating.

The task of developing ESC/EAS Guidelines also includes the creation of
educational tools and implementation programmes for the recommendations
including condensed pocket guideline versions, summary slides, booklets with
essential messages, summary cards for non-specialists and an electronic version
for digital applications (smartphones, etc.). These versions are abridged and
thus, for more detailed information, the user should always access the full text
version of the Guidelines, which is freely available via the ESC and EAS
websites and hosted on their journals’ websites (EHJ and Atherosclerosis
Journal). The National Cardiac Societies of the ESC are encouraged to endorse,
translate and implement all ESC Guidelines. Implementation programmes are needed
because it has been shown that the outcome of disease may be favourably
influenced by the thorough application of clinical recommendations.

Health professionals are encouraged to take the ESC/EAS Guidelines fully into
account when exercising their clinical judgment, as well as in the determination
and the implementation of preventive, diagnostic or therapeutic medical
strategies. However, the ESC/EAS Guidelines do not override in any way
whatsoever the individual responsibility of health professionals to make
appropriate and accurate decisions in consideration of each patient's health
condition and in consultation with that patient or the patient's caregiver where
appropriate and/or necessary. It is also the health professional's
responsibility to verify the rules and regulations applicable in each country to
drugs and devices at the time of prescription.

2 INTRODUCTION

The previous ESC/EAS lipid Guidelines were published in August 2016.1 The
emergence of a substantial body of evidence over the last few years has required
new, up-to-date Guidelines.

New evidence has confirmed that the key initiating event in atherogenesis is the
retention of low-density lipoprotein (LDL) cholesterol (LDL-C) and other
cholesterol-rich apolipoprotein (Apo) B-containing lipoproteins within the
arterial wall.2 Several recent placebo-controlled clinical studies have shown
that the addition of either ezetimibe or anti-proprotein convertase
subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) to statin therapy
provides a further reduction in atherosclerotic cardiovascular disease (ASCVD)
risk, which is directly and positively correlated with the incrementally
achieved absolute LDL-C reduction. Furthermore, these clinical trials have
clearly indicated that the lower the achieved LDL-C values, the lower the risk
of future cardiovascular (CV) events, with no lower limit for LDL-C values, or
‘J’-curve effect. In addition, studies of the clinical safety of these very low
achieved LDL-C values have proved reassuring, albeit monitoring for longer
periods is required. For raising high-density lipoprotein (HDL) cholesterol
(HDL-C), recent studies have indicated that the currently available therapies do
not reduce the risk of ASCVD. Finally, human Mendelian randomization studies
have demonstrated the critical role of LDL-C, and other cholesterol-rich
ApoB-containing lipoproteins, in atherosclerotic plaque formation and related
subsequent CV events. Thus, there is no longer an ‘LDL-C hypothesis’, but
established facts that increased LDL-C values are causally related to ASCVD, and
that lowering LDL particles and other ApoB-containing lipoproteins as much as
possible reduces CV events.

In order to be aligned with these new findings, the ESC/EAS Task Force members
who have written these Guidelines have proposed new LDL-C goals, as well as a
revised CV risk stratification, which are especially relevant to high- and
very-high-risk patients.

These novel ESC/EAS Guidelines on lipids provide important new advice on patient
management, which should enable more clinicians to efficiently and safely reduce
CV risk through lipid modification.

2.1 WHAT IS NEW IN THE 2019 GUIDELINES?

New recommendations, and new and revised concepts, are presented in Table 3.

Table 3

New recommendations, and new and revised concepts

ACS = acute coronary syndrome; ApoB = apolipoprotein B; ASCVD = atherosclerotic
cardiovascular disease; CAC = coronary artery calcium; CHD = coronary heart
disease; CT = computed tomography; CV = cardiovascular; CVD = cardiovascular
disease; DM = diabetes mellitus; FH = familial hypercholesterolaemia; HDL =
high-density lipoprotein; LDL-C = low-density lipoproteins cholesterol; Lp(a) =
lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9; PUFAs =
polyunsaturated fatty acids; RCTs = randomized controlled trials; T1DM = type 1
diabetes mellitus; T2DM = type 2 diabetes mellitus; TGs = triglycerides.

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Table 3

New recommendations, and new and revised concepts

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3 WHAT IS CARDIOVASCULAR DISEASE PREVENTION?

3.1 DEFINITION AND RATIONALE

Cardiovascular disease (CVD), of which ASCVD is the major component, is
responsible for >4 million deaths in Europe each year. It kills more women (2.2
million) than men (1.8 million), although CV deaths before the age of 65 years
are more common in men (490 000 vs. 193 000).3 Prevention is defined as a
co-ordinated set of actions, either at the population or individual level, aimed
at eliminating or minimizing the impact of CV diseases and their related
disabilities. More patients are surviving their first CVD event and are at
high-risk of recurrences. In addition, the prevalence of some risk factors,
notably diabetes (DM) and obesity, is increasing. The importance of ASCVD
prevention remains undisputed and should be delivered at the general population
level by promoting healthy lifestyle behaviour,4 and at the individual level by
tackling unhealthy lifestyles and by reducing increased levels of causal CV risk
factors, such as LDL cholesterol or blood pressure (BP) levels.

3.2 DEVELOPMENT OF THE JOINT TASK FORCE GUIDELINES FOR THE MANAGEMENT OF
DYSLIPIDAEMIAS

The present Guidelines represent an evidence-based consensus of the European
Task Force, including the ESC and the EAS.

By appraising the current evidence and identifying remaining knowledge gaps in
the management of dyslipidaemias, the Task Force has formulated recommendations
to guide action in clinical practice to prevent ASCVD by modifying plasma lipid
levels.

This document has been developed for healthcare professionals to facilitate
informed communication with individuals about their CV risk and the benefits of
adopting and sustaining a healthy lifestyle, and of early modification of their
lipid-related CV risk. In addition, the Guidelines provide tools for healthcare
professionals to promote up-to-date intervention strategies, integrate these
strategies into national or regional prevention frameworks, and to translate
them into locally delivered healthcare services, in line with the
recommendations of the World Health Organization (WHO) Global Status Report on
Noncommunicable Diseases 2014.5

A lifetime approach to CV risk should be considered.1 This implies that—apart
from improving lifestyle habits and reducing risk factor levels in patients with
established ASCVD, and in those at increased risk of developing ASCVD—people of
all ages should be encouraged to adopt or sustain a healthy lifestyle.

4 TOTAL CARDIOVASCULAR RISK

4.1 TOTAL CARDIOVASCULAR RISK ESTIMATION

CV risk in the context of these Guidelines means the likelihood of a person
developing an atherosclerotic CV event over a defined period of time. Total CVD
risk expresses the combined effect of a number of risk factors on this risk
estimate. In these Guidelines, we address the lipid-related contribution to
total CV risk and how to manage it at the clinical level.

4.1.1 RATIONALE FOR ASSESSING TOTAL CARDIOVASCULAR DISEASE RISK

All current guidelines on the prevention of ASCVD in clinical practice recommend
the assessment of total CVD risk. Prevention of ASCVD in a given person should
relate to his or her total CV risk: the higher the risk, the more intense the
action should be.

Many risk assessment systems are available and have been comprehensively
reviewed (Supplementary Table 1 in the Supplementary Data). Most guidelines use
one of these risk assessment systems.6–8 Ideally, risk charts should be based on
country-specific cohort data. These are not available for most countries. The
SCORE (Systematic Coronary Risk Estimation) system can be recalibrated for use
in different populations by adjusting for secular changes in CVD mortality and
risk factor prevalence. Calibrated country-specific versions are available for
many European countries and can be found at http://www.heartscore.org. These are
now being updated to provide recalibrated, contemporaneous country-specific
charts for all European countries. Other risk estimation systems—using both
fatal and non-fatal events—can also be recalibrated, but the process is easier
and scientifically more robust for mortality than for total events. The European
Guidelines on CVD prevention in clinical practice (both the 20129 and 201610
versions) recommend the use of the SCORE system because it is based on large,
representative European cohort data sets and because it is relatively
straightforward to recalibrate for individual countries.

Persons with documented ASCVD, type 1 or type 2 DM (T1DM and T2DM,
respectively), very high levels of individual risk factors, or chronic kidney
disease (CKD) are generally at very-high or high total CV risk. No risk
estimation models are needed for such persons; they all need active management
of all risk factors. For other, apparently healthy people, the use of a risk
estimation system such as SCORE, which estimates the 10 year cumulative risk of
a first fatal atherosclerotic event, is recommended to estimate total CV risk,
since many people have several risk factors that, in combination, may result in
high levels of total CV risk.

Risk estimates have been produced as charts for high- and low-risk regions in
Europe (Figures 1 and 2).11 All International Classification of Diseases codes
that are related to deaths from vascular origin caused by atherosclerosis are
included. The reasons for retaining a system that estimates fatal as opposed to
total fatal + non-fatal events are that non-fatal events are dependent on
definition, developments in diagnostic tests, and methods of ascertainment, all
of which can vary, resulting in very variable multipliers to convert fatal to
total events. In addition, total event charts, in contrast to those based on
mortality, are more difficult to recalibrate to suit different populations. That
said, work is in progress to produce regional total event charts.

Figure 1
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Systematic Coronary Risk Estimation chart for European populations at high
cardiovascular disease risk. The 10-year risk of fatal cardiovascular disease in
populations at high cardiovascular disease risk based on the following risk
factors: age, gender, smoking, systolic blood pressure, and total cholesterol.
To convert the risk of fatal cardiovascular disease to risk of total (fatal +
non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women, and
slightly less in older people. Note: the Systematic Coronary Risk Estimation
chart is for use in people without overt cardiovascular disease, diabetes (type
1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high
levels of individual risk factors because such people are already at high-risk
and need intensive risk factor management. Cholesterol: 1 mmol/L = 38.67 mg/dL.
The SCORE risk charts presented above differ slightly from those in the 2016
European Society of Cardiology/European Atherosclerosis Society Guidelines for
the management of dyslipidaemias and the 2016 European Guidelines on
cardiovascular disease prevention in clinical practice, in that: (i) age has
been extended from age 65 to 70; (ii) the interaction between age and each of
the other risk factors has been incorporated, thus reducing the overestimation
of risk in older persons in the original Systematic Coronary Risk Estimation
charts; and (iii) the cholesterol band of 8 mmol/L has been removed, since such
persons will qualify for further evaluation in any event. SCORE = Systematic
Coronary Risk Estimation.

Figure 2
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Systematic Coronary Risk Estimation chart for European populations at low
cardiovascular disease risk. The 10-year risk of fatal cardiovascular disease in
populations at low cardiovascular disease risk based on the following risk
factors: age, gender, smoking, systolic blood pressure, and total cholesterol.
To convert the risk of fatal cardiovascular disease to risk of total (fatal +
non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women, and
slightly less in older people. Note: the Systematic Coronary Risk Estimation
chart is for use in people without overt cardiovascular disease, diabetes (type
1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high
levels of individual risk factors because such people are already at high-risk
and need intensive risk factor management. Cholesterol: 1 mmol/L=38.67 mg/dL.
The SCORE risk charts presented above differ slightly from those in the 2016
European Society of Cardiology/European Atherosclerosis Society Guidelines for
the management of dyslipidaemias and the 2016 European Guidelines on
cardiovascular disease prevention in clinical practice, in that: (i) age has
been extended from age 65 to 70; (ii) the interaction between age and each of
the other risk factors has been incorporated, thus reducing the overestimation
of risk in older persons in the original Systematic Coronary Risk Estimation
charts; and (iii) the cholesterol band of 8 mmol/L has been removed since such
persons will qualify for further evaluation in any event. SCORE = Systematic
Coronary Risk Estimation.

The SCORE data indicate that the total CVD event risk is about three times
higher than the risk of fatal CVD for men, so a SCORE risk of 5% translates into
a CVD risk of ∼15% of total (fatal + non-fatal) CVD endpoints; the multiplier is
higher in women and lower in older people.

Clinicians often ask for thresholds to trigger certain interventions. This is
problematic since risk is a continuum and there is no threshold at which, for
example, a drug is automatically indicated. This is true for all continuous risk
factors such as plasma cholesterol or systolic BP (SBP). Therefore, the goals
that are proposed in this document reflect this concept.

A particular problem relates to young people with high levels of risk factors; a
low absolute risk may conceal a very high relative risk requiring at least
intensive lifestyle advice. To motivate young people (i.e. aged <40 years) not
to delay changing their unhealthy lifestyle, an estimate of their relative
risk—illustrating that lifestyle changes can reduce relative risk
substantially—may be helpful (Supplementary Figure 1).

Another approach to this problem is to use CV risk age. The risk age of a person
with several CV risk factors is the age of a person with the same level of risk
but with ideal levels of risk factors. Thus, a high-risk 40-year-old would have
a risk age ≥65 years. Risk age can be estimated visually by looking at the SCORE
chart (as illustrated in Supplementary Figure 2). In this chart, the risk age of
a person with risk factors is defined as the age at which a person with ideal
risk factor levels would reach the same risk level. Ideal risk factors are
non-smoking, total cholesterol (TC) ≤4 mmol/L (≤155 mg/dL), and SBP ≤120 mmHg.
Risk age is also automatically calculated as part of the latest revision of
HeartScore (http://www.HeartScore.org).

Risk age has been shown to be independent of the CV endpoint used,6,8 can be
used in any population regardless of baseline risk or secular changes in
mortality, and therefore avoids the need for recalibration.

Lifetime risk is another approach to illustrate the impact of risk factors that
may be useful in younger people.12 The greater the burden of risk factors, the
higher the lifetime risk. This approach produces higher risk figures for younger
people because of their longer exposure times. Therefore, it is more useful as a
way of illustrating risk than as a guide to treatment, because therapeutic
trials have been based on a fixed follow-up period and not on lifetime risk.

Another problem relates to older people. In some age categories, the majority of
people, especially males, will have estimated 10 year cumulative CV death risks
exceeding the 5–10% level, based on age only, even when other CV risk factor
levels are relatively low. Therefore, before initiating treatment in the
elderly, clinicians should evaluate patients carefully. The relative strengths
of risk factors vary with age and SCORE overestimates risk in older people (that
is, those aged >65 years).11 These Guidelines include illustrative charts for
older people (see Figures 1 and 2). While older people benefit from smoking
cessation, and control of hypertension and hyperlipidaemia (see section 9.3),
clinical judgement is required to avoid side effects from overmedication.

The additional impact of HDL-C on risk estimation is illustrated in
Supplementary Figures 3 and 4; HDL-C can be used to increase the accuracy of the
risk evaluation. In these charts, HDL-C is used categorically. The electronic
version of SCORE, HeartScore (http://www.heartscore.org/en_GB/), has been
modified to take HDL-C into consideration as a continuous variable. Clinicians
should be aware that at extremely high values [above ∼2.3 mmol/L (90 mg/dL)] of
HDL-C there appears to be an increased risk of ASCVD, so at such levels HDL-C
cannot be used as a risk predictor.

4.1.2 HOW TO USE THE RISK ESTIMATION CHARTS

Use of the low- or the high-risk SCORE charts will depend on the CVD mortality
experience in each country. While any cut-off point is arbitrary and open to
debate, in these Guidelines, the cut-off point for calling a country ‘low CVD
risk’ is based on WHO data derived from the Global Burden of Disease Study.

Countries are categorized as low-risk if their age-adjusted 2016 CVD mortality
rate was <150/100 000 (for men and women together)
(http://www.who.int/healthinfo/global_burden_disease/estimates/en/). Countries
with a CVD mortality rate of ≥150/100 000 or more are considered to be at
high-risk.

Boxes 1 to 5 summarize the main points regarding the risk estimation charts and
their use.

Box 1

How to use the risk estimation charts

To estimate a person’s 10-year risk of CVD death, find the table for his/her
gender, smoking status, and age. Within the table, find the cell nearest to the
person’s BP and TC. Risk estimates will need to be adjusted upwards as the
person approaches the next age category. Risk is initially assessed on the level
of TC and systolic BP before treatment, if known. The longer the treatment and
the more effective it is, the greater the reduction in risk, but in general it
will not be more than about one-third of the baseline risk. For example, for a
person on antihypertensive drug treatment in whom the pre-treatment BP is not
known, if the total CV SCORE risk is 6%, then the pre-treatment total CV risk
may have been 9%. Low-risk persons should be offered advice to maintain their
low-risk status. While no threshold is universally applicable, the intensity of
advice should increase with increasing risk. The charts may be used to give some
indication of the effects of reducing risk factors, given that there is
apparently a time lag before the risk reduces. In general, people who stop
smoking halve their cumulative risk over a relatively short period of time.

BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; SCORE =
Systematic Coronary Risk Estimation; TC = total cholesterol.

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Box 1

How to use the risk estimation charts

BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; SCORE =
Systematic Coronary Risk Estimation; TC = total cholesterol.

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Box 2

Risk estimation charts for different countries

The low-risk charts should be considered for use in Austria, Belgium, Cyprus,
Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy,
Luxembourg, Netherlands, Norway, Malta, Portugal, Slovenia, Spain, Sweden,
Switzerland, and the UK. The high-risk charts should be considered for use in
Albania, Algeria, Armenia, Bosnia and Herzegovina, Croatia, Czech Republic,
Estonia, Hungary, Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco,
Poland, Romania, Serbia, Slovakia, Tunisia, and Turkey. Some countries have a
cardiovascular disease mortality rate >350/100 000, and the high-risk chart may
underestimate risk. These are Azerbaijan, Belarus, Bulgaria, Egypt, Georgia,
Kazakhstan, Kyrgyzstan, North Macedonia, Republic of Moldova, Russian
Federation, Syria, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan.

See http://apps.who.int/gho/data/node.home.

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Box 2

Risk estimation charts for different countries

See http://apps.who.int/gho/data/node.home.

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Box 3

Qualifiers

The charts can assist in risk assessment and management, but must be interpreted
in light of the clinician’s knowledge and experience, and of the patient’s
pre-test likelihood of CVD. Risk will be overestimated in countries with
decreasing CVD mortality, and underestimated in countries in which mortality is
increasing. This is dealt with by recalibration
(http://www.heartscore.org/en_GB/). Risk estimates are lower in women than in
men. However, risk is only deferred in women; the risk of a 60-year-old woman is
similar to that of a 50-year-old man. Ultimately, more women die from CVD than
men. Relative risks may be unexpectedly high in young persons, even if absolute
risk levels are low. The relative risk chart (Supplementary Figure 1) and the
estimated risk age (Supplementary Figure 2) may be helpful in identifying and
counselling such persons.

CVD = cardiovascular disease.

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Box 3

Qualifiers

CVD = cardiovascular disease.

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Box 4

Factors modifying Systematic Coronary Risk Estimation risks

Social deprivation: the origin of many of the causes of CVD. Obesity and central
obesity as measured by the body mass index and waist circumference,
respectively. Physical inactivity. Psychosocial stress including vital
exhaustion. Family history of premature CVD (men: <55 years and women: <60
years). Chronic immune-mediated inflammatory disorder. Major psychiatric
disorders. Treatment for human immunodeficiency virus infection. Atrial
fibrillation. Left ventricular hypertrophy. Chronic kidney disease. Obstructive
sleep apnoea syndrome. Non-alcoholic fatty liver disease.

CVD = cardiovascular disease.

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Box 4

Factors modifying Systematic Coronary Risk Estimation risks

CVD = cardiovascular disease.

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Social deprivation and psychosocial stress set the scene for increased risk.13
For those at moderate risk, other factors—including metabolic factors such as
increased ApoB, lipoprotein(a) [Lp(a)], triglycerides (TGs), or C-reactive
protein; the presence of albuminuria; the presence of atherosclerotic plaque in
the carotid or femoral arteries; or the coronary artery calcium (CAC) score—may
improve risk classification. Many other biomarkers are also associated with
increased CVD risk, although few of these have been shown to be associated with
appreciable reclassification. Total CV risk will also be higher than indicated
in the SCORE charts in asymptomatic persons with abnormal markers of subclinical
atherosclerotic vascular damage. Reclassification is of value in people
identified as being at moderate CV risk by using markers such as CAC score >100
Agatston units, ankle–brachial index (ABI) <0.9 or >1.40, carotid–femoral pulse
wave velocity >10 m/s, or the presence of plaques at carotid or femoral
ultrasonography. In studies comparing these markers, CAC had the best
reclassification ability.14–16

Some factors such as a high HDL-C up to 2.3 mmol/L (90mg/dL)17 or a family
history of longevity can also be associated with lower risk.

Box 5

Risk estimation: key messages

In apparently healthy persons, CVD risk is most frequently the result of
multiple, interacting risk factors. This is the basis for total CV risk
estimation and management. Risk factor screening including the lipid profile
should be considered in men >40 years old, and in women >50 years of age or
post-menopausal. A risk estimation system such as SCORE can assist in making
logical management decisions, and may help to avoid both under- and
overtreatment. Certain individuals declare themselves to be at high or very high
CVD risk without needing risk scoring, and all risk factors require immediate
attention. This is true for patients with documented CVD, older individuals with
long-standing DM, familial hypercholesterolaemia, chronic kidney disease,
carotid or femoral plaques, coronary artery calcium score >100, or extreme Lp(a)
elevation. All risk estimation systems are relatively crude and require
attention to qualifying statements. Additional factors affecting risk can be
accommodated in electronic risk estimation systems such as HeartScore
(www.heartscore.org). The total risk approach allows flexibility; if optimal
control cannot be achieved with one risk factor, trying harder with the other
factors can still reduce risk.

CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; SCORE
= Systematic Coronary Risk Estimation.

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Box 5

Risk estimation: key messages

CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; SCORE
= Systematic Coronary Risk Estimation.

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4.2 RISK LEVELS

A total CV risk estimate is part of a continuum. The cut-off points that are
used to define high-risk are, in part, both arbitrary and based on the risk
levels at which benefit is evident in clinical trials. In clinical practice,
consideration should be given to practical issues in relation to the local
healthcare systems. Not only should those at high risk be identified and
managed, but those at moderate risk should also receive professional advice
regarding lifestyle changes; in some cases, drug therapy will be needed to
reduce atherosclerotic risk.

Low-risk people should be given advice to help them maintain this status. Thus,
the intensity of preventive actions should be tailored to the patient’s total CV
risk. The strongest driver of total CV risk is age, which can be considered as
‘exposure time’ to risk factors.

For these reasons, the Task Force suggests the following categories of risk and
LDL-C goals, based on the best available evidence and in an ideal setting with
unlimited resources. These categories represent a counsel of perfection, but
these ideals are for guidance only and practical decision-making must be based
on what is appropriate to the local situation.

With these considerations, we propose the levels of total CV risk presented in
Table 4.

Table 4

Cardiovascular risk categories

ASCVD = atherosclerotic cardiovascular disease; ACS = acute coronary syndrome;
BP = blood pressure; CABG = coronary artery bypass graft surgery; CKD = chronic
kidney disease; CT = computed tomography; CVD = cardiovascular disease; DM =
diabetes mellitus; eGFR = estimated glomerular filtration rate; FH = familial
hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; MI =
myocardial infarction; PCI = percutaneous coronary intervention; SCORE =
Systematic Coronary Risk Estimation; T1DM = type 1 DM; T2DM = type 2 DM; TC =
total cholesterol; TIA = transient ischaemic attack.

Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy.

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Table 4

Cardiovascular risk categories

Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy.

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4.2.1 ROLE OF NON-INVASIVE CARDIOVASCULAR IMAGING TECHNIQUES IN THE ASSESSMENT
OF TOTAL CARDIOVASCULAR DISEASE RISK

Non-invasive imaging techniques can detect the presence, estimate the extent,
and evaluate the clinical consequences of atherosclerotic vascular damage.
Detection of coronary artery calcification with non-contrast computed tomography
(CT) gives a good estimate of the atherosclerotic burden and is strongly
associated with CV events.18 A recent meta-analysis from the US Preventive
Services Task Force summarized the available evidence on the value of
non-traditional risk factors for risk prediction, and found that, although there
are no randomized trials showing that the use of CAC reduces health outcomes,
nevertheless it improves both discrimination and reclassification.19 Assessment
of carotid or femoral plaque burden with ultrasound has also been demonstrated
to be predictive of CV events, comparable to CAC,20–23 while the measurement of
the carotid intima–media thickness is inferior to CAC score and carotid plaque
detection.16,24,25

In asymptomatic patients at low or moderate risk who would be eligible for
statin therapy (see Table 5), assessment of ASCVD with imaging may have an
impact on medical treatment, both from the physician’s and the patient’s points
of view. Data from the Multi-Ethnic Study of Atherosclerosis (MESA) showed that
41–57% of individuals who would be eligible for statin therapy had a CAC score
of zero and the rate of atherosclerotic CVD events in the 10 year follow-up
period was low (1.5–4.9%).26 In contrast, the rates of ASCVD and coronary heart
disease (CHD) events in individuals with a CAC score >100 Agatston were 18.9 and
12.7 per 1000 person-years, respectively.18 Compared with a strategy of treating
all patients, the use of CAC score to guide long-term statin therapy has been
shown to be cost-effective.27 Note that CAC score is often very low in patients
younger than 45 years of age with severe familial hypercholesterolaemia (FH),
including homozygous FH (HoFH), and has low specificity in this population.

Assessment of coronary luminal stenosis >50% and plaque composition with
coronary CT angiography also provides incremental prognostic value over
traditional risk stratification models.28 As a result, in asymptomatic
individuals with moderate risk, the presence of a CAC score >100 Agatston, and
carotid or femoral plaque burden on ultrasonography, may reclassify them to a
higher risk category. Therefore, the use of methods to detect these markers
should be of interest in that group (see Recommendations for cardiovascular
imaging for risk assessment of atherosclerotic cardiovascular disease
below).14–16 Overall, CAC score assessment with CT may be considered in
individuals at low or moderate risk in whom the respective LDL-C goal is not
achieved with lifestyle intervention alone, and pharmacological therapy is an
option (see Table 5). The use of imaging techniques to determine the presence
and extent of atherosclerotic vascular damage in low-risk individuals not being
considered for statin therapy is not justified due to low prognostic yield, and
the associated costs and radiation hazards when measuring CAC score,
particularly among low-risk women.29 Of note, CAC score is increased following
statin treatment; therefore, the CAC scores of statin-treated patients should be
interpreted with caution.

Recommendations for cardiovascular imaging for risk assessment of
atherosclerotic cardiovascular disease

CAC = coronary artery calcium; CT = computed tomography; CV = cardiovascular.

Class of recommendation.

Level of evidence.

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Recommendations for cardiovascular imaging for risk assessment of
atherosclerotic cardiovascular disease

CAC = coronary artery calcium; CT = computed tomography; CV = cardiovascular.

Class of recommendation.

Level of evidence.

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4.2.2 RISK-BASED INTERVENTION STRATEGIES

Table 5 presents suggested intervention strategies as a function of total CV
risk and LDL-C level. This graded approach is based on evidence from multiple
meta-analyses and individual randomized controlled trials (RCTs), which show a
consistent and graded reduction in ASCVD risk in response to reductions in TC
and LDL-C levels (see Recommendations for cardiovascular disease risk estimation
below).31–41 These data are consistent in showing that, since the relative risk
reduction is proportional to the absolute reduction in LDL-C and the absolute
reduction in LDL-C resulting from a particular drug regimen depends only on
baseline LDL-C, at any given level of baseline risk the higher the initial LDL-C
level the greater the absolute reduction in risk. Advice on individual drug
treatments is given in section 8.

Table 5

Intervention strategies as a function of total cardiovascular risk and untreated
low-density lipoprotein cholesterol levels

CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; SCORE =
Systematic Coronary Risk Estimation.

Class of recommendation.

Level of evidence.

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Table 5

Intervention strategies as a function of total cardiovascular risk and untreated
low-density lipoprotein cholesterol levels

CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; SCORE =
Systematic Coronary Risk Estimation.

Class of recommendation.

Level of evidence.

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Recommendations for cardiovascular disease risk estimation

CKD = chronic kidney disease; CV= cardiovascular; CVD = cardiovascular disease;
DM = diabetes mellitus; FH = familial hypercholesterolaemia; LDL-C = low-density
lipoprotein cholesterol; SCORE = Systematic Coronary Risk Estimation.

Class of recommendation.

Level of evidence.

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Recommendations for cardiovascular disease risk estimation

Class of recommendation.

Level of evidence.

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5 LIPIDS AND LIPOPROTEINS

5.1 BIOLOGICAL ROLE OF LIPIDS AND LIPOPROTEINS

Lipoproteins in plasma transport lipids to tissues for energy utilization, lipid
deposition, steroid hormone production, and bile acid formation. Lipoproteins
consist of esterified and unesterified cholesterol, TGs, and phospholipids and
protein components named apolipoproteins that act as structural components,
ligands for cellular receptor binding, and enzyme activators or inhibitors.

There are six major lipoproteins in blood: chylomicrons, very low-density
lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL; Lp(a), and HDL
(Table 6 and Supplementary Figure 5).

Table 6

Physical and chemical characteristics of human plasma lipoproteins

. Density (g/mL) . Diameter (nm) . TGs (%) . Cholesteryl esters (%) . PLs (%)
. Cholesterol (%) . Apolipoproteins

--------------------------------------------------------------------------------

. Major . Others . Chylomicrons <0.95 80–100 90–95 2–4 2–6 1 ApoB-48 ApoA-I,
A-II, A-IV, A-V VLDL 0.95–1.006 30–80 50–65 8–14 12–16 4–7 ApoB-100 ApoA-I,
C-II, C-III, E,
A-V IDL 1.006–1.019 25–30 25–40 20–35 16–24 7–11 ApoB-100 ApoC-II, C-III,
E LDL 1.019–1.063 20–25 4–6 34–35 22–26 6–15 ApoB-100 HDL 1.063–1.210 8–13 7 10–20 55 5 ApoA-I ApoA-II,
C-III, E, M Lp(a) 1.006–1.125 25–30 4–8 35–46 17–24 6–9 Apo(a) ApoB-100

. Density (g/mL) . Diameter (nm) . TGs (%) . Cholesteryl esters (%) . PLs (%)
. Cholesterol (%) . Apolipoproteins

--------------------------------------------------------------------------------

Apo = apolipoprotein; HDL = high-density lipoprotein; IDL = intermediate-density
lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); PLs =
phospholipids; TGs = triglycerides; VLDL = very low-density lipoprotein.

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Table 6

Physical and chemical characteristics of human plasma lipoproteins

. Density (g/mL) . Diameter (nm) . TGs (%) . Cholesteryl esters (%) . PLs (%)
. Cholesterol (%) . Apolipoproteins

--------------------------------------------------------------------------------

. Density (g/mL) . Diameter (nm) . TGs (%) . Cholesteryl esters (%) . PLs (%)
. Cholesterol (%) . Apolipoproteins

--------------------------------------------------------------------------------

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5.2 ROLE OF LIPIDS AND LIPOPROTEINS IN THE PATHOPHYSIOLOGY OF ATHEROSCLEROSIS

All ApoB-containing lipoproteins <70 nm in diameter, including smaller TG-rich
lipoproteins and their remnant particles, can cross the endothelial barrier,
especially in the presence of endothelial dysfunction, where they can become
trapped after interaction with extracellular structures such as proteoglycans.42
ApoB-containing lipoproteins retained in the arterial wall provoke a complex
process that leads to lipid deposition and the initiation of an atheroma.43

Continued exposure to ApoB-containing lipoproteins leads to additional particles
being retained over time in the artery wall, and to the growth and progression
of atherosclerotic plaques. On average, people with higher concentrations of
plasma ApoB-containing lipoproteins will retain more particles and accumulate
lipids faster, resulting in more rapid growth and the progression of
atherosclerotic plaques.

Because atherosclerotic plaques grow over time as additional ApoB-containing
lipoprotein particles are retained, the size of the total atherosclerotic plaque
burden is likely to be determined by both the concentration of circulating LDL-C
and other ApoB-containing lipoproteins, and by the total duration of exposure to
these lipoproteins. Therefore, a person’s total atherosclerotic plaque burden is
likely to be proportional to the cumulative exposure to these lipoproteins.44

Eventually, the increase of the atherosclerotic plaque burden along with changes
in the composition of the plaque reaches a critical point at which disruption of
a plaque can result, with the formation of an overlying thrombus that acutely
obstructs blood flow resulting in unstable angina, myocardial infarction (MI),
or death. Therefore, the risk of experiencing an acute ASCVD event rises rapidly
as more ApoB-containing lipoproteins become retained and the atherosclerotic
plaque burden increases. This provides the rationale for encouraging a healthy
lifestyle to maintain low levels of ApoB-containing lipoproteins throughout life
to slow the progression of atherosclerosis; it also explains the motivation to
recommend treatment to lower LDL-C and other ApoB-containing lipoproteins, for
both the primary prevention of ASCVD and the secondary prevention of recurrent
CV events.44

5.3 EVIDENCE FOR THE CAUSAL EFFECTS OF LIPIDS AND LIPOPROTEINS ON THE RISK OF
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

5.3.1 LOW-DENSITY LIPOPROTEIN CHOLESTEROL AND RISK OF ATHEROSCLEROSIS

Plasma LDL-C is a measure of the cholesterol mass carried by LDL particles, by
far the most numerous of the ApoB-containing lipoproteins, and is an estimate of
the concentration of circulating LDL. Numerous epidemiological studies,
Mendelian randomization studies, and RCTs have consistently demonstrated a
log-linear relationship between the absolute changes in plasma LDL-C and the
risk of ASCVD.34,45–50 The remarkable consistency among these studies, in
addition to biological and experimental evidence, provides compelling evidence
that LDL-C is causally associated with the risk of ASCVD, and that lowering
LDL-C reduces the risk of ASCVD proportionally to the absolute achieved
reduction in LDL-C.2,51

Furthermore, Mendelian randomization studies have demonstrated that long-term
exposure to lower LDL-C levels is associated with a much lower risk of CV events
as compared with shorter-term exposure to lower LDL-C (as achieved, for example,
in randomized trials).48,52 These data provide strong support for the concept
that LDL particles have both a causal and cumulative effect on the risk of
ASCVD. Therefore, the effect of LDL-C on the risk of ASCVD appears to be
determined by both the absolute magnitude and the total duration of exposure to
LDL-C.2

The clinical benefit of lowering LDL-C is determined by the reduction in
circulating LDL particles as estimated by ApoB, which is usually mirrored by a
reduction of cholesterol carried by those particles.2,53 Therefore, the clinical
benefit of therapies that lower LDL-C by reducing LDL particle mass will be
proportional to the absolute reduction in LDL-C, because—on average—the
reduction in LDL-C and LDL particles will be concordant.34,50,54,55 In contrast,
the clinical benefit of therapies that lower LDL-C by a mechanism that may
dramatically modify their composition may not be proportional to the observed
absolute reduction in LDL-C, but instead would be expected to be proportional to
the absolute change in LDL particle concentration as measured by a reduction in
ApoB.2,53

5.3.2 TRIGLYCERIDE-RICH LIPOPROTEINS AND RISK OF ATHEROSCLEROSIS

TG-rich VLDL particles and their remnants carry most of the circulating TGs.
Therefore, the plasma TG concentration reflects the concentration of circulating
ApoB-containing TG-rich lipoproteins.

Elevated plasma TG levels are associated with an increasing risk of ASCVD, but
this association becomes null after adjusting for non-HDL-C, an estimate of the
total concentration of all ApoB-containing lipoproteins.45 Similarly, lowering
TG with fibrates reduces the risk of CV events by the same amount as
LDL-C-lowering therapies when measured per unit change of non-HDL-C,50
suggesting that the effect of plasma TGs on ASCVD is mediated by changes in the
concentration of TG-rich lipoproteins as estimated by non-HDL-C.

Mendelian randomization studies also suggest that the association between plasma
TGs and the risk of CHD may be causal; however, this evidence must be
interpreted with caution because nearly all variants associated with TGs are
also associated with HDL-C, LDL-C, or Lp(a).56–59 A recent Mendelian
randomization study demonstrated that TG-lowering lipoprotein lipase (LPL)
variants and LDL-C-lowering LDL receptor variants had the same effect on the
risk of ASCVD per unit change of ApoB, suggesting that all ApoB-containing
lipoproteins have the same effect on the risk of CHD.53 Together, these studies
strongly suggest that the causal effect of TG-rich lipoproteins and their
remnants on the risk of ASCVD is determined by the circulating concentration of
ApoB-containing particles, rather than by the TG content itself.

5.3.3 HIGH-DENSITY LIPOPROTEIN CHOLESTEROL AND RISK OF ATHEROSCLEROSIS

The inverse association between plasma HDL-C and the risk of ASCVD is among the
most consistent and reproducible associations in observational
epidemiology.45,60 In contrast, Mendelian randomization studies do not provide
compelling evidence that HDL-C is causally associated with the risk of
ASCVD.49,61,62 However, this evidence must be interpreted with caution because
most genetic variants associated with HDL-C are also associated with
directionally opposite changes in TGs, LDL-C, or both, thus making estimates of
the effect of HDL-C on the risk of ASCVD very difficult using the Mendelian
randomization study design. Furthermore, there is no evidence from randomized
trials that therapeutically increasing plasma HDL-C reduces the risk of CV
events.63–67 In the Effects of Dalcetrapib in Patients with a Recent Acute
Coronary Syndrome (dal-OUTCOMES) trial, treatment with the cholesteryl ester
transfer protein (CETP) inhibitor dalcetrapib increased HDL-C without any effect
on LDL-C or ApoB, but did not reduce the risk of major CV events.65 Similarly,
in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein
Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes
(ACCELERATE) and Randomized Evaluation of the Effects of Anacetrapib Through
Lipid Modification (REVEAL) trials, treatment with CETP inhibitors more than
doubled HDL-C levels, but did not appear to reduce the risk of ASCVD events
beyond that expected from the modest reductions in ApoB levels.2,63,64
Furthermore, several randomized trials have shown that directly infused HDL
mimetics increase plasma HDL-C concentrations, but do not reduce the progression
of atherosclerosis as measured by intravascular ultrasound.68,69

Therefore, there is currently no randomized trial or genetic evidence to suggest
that raising plasma HDL-C is likely to reduce the risk of ASCVD events. Whether
therapies that alter the function of HDL particles will reduce the risk of ASCVD
is unknown.

5.3.4 LIPOPROTEIN(A) AND RISK OF ATHEROSCLEROSIS

Lp(a) is an LDL particle with an Apo(a) moiety covalently bound to its ApoB
component.70 It is <70 nm in diameter and can freely flux across the endothelial
barrier, where it can become—similarly to LDL—retained within the arterial wall
and thus may increase the risk of ASCVD. Pro-atherogenic effects of Lp(a) have
also been attributed to pro-coagulant effects as Lp(a) has a similar structure
to plasminogen, and it has pro-inflammatory effects most likely related to the
oxidized phospholipid load carried by Lp(a).71

Higher plasma Lp(a) concentrations are associated with an increased risk of
ASCVD, but it appears to be a much weaker risk factor for most people than
LDL-C.72,73 In contrast, Mendelian randomization studies have consistently
demonstrated that lifelong exposure to higher Lp(a) levels is strongly and
causally associated with an increased risk of ASCVD.74,75 While randomized
trials evaluating therapies that lower Lp(a) by 20–30% (including niacin and
CETP inhibitors) have not provided evidence that lowering Lp(a) reduces the risk
of ASCVD beyond that which would be expected from the observed reduction in
ApoB-containing lipoproteins, recent data with PCSK9 inhibitors have suggested a
possible role for Lp(a) lowering in reducing CV risk.76

This conflicting evidence appears to have been reconciled by a recent Mendelian
randomization study that showed that the causal effect of Lp(a) on the risk of
ASCVD is proportional to the absolute change in plasma Lp(a) levels.
Importantly, this study also suggested that people with extremely high Lp(a)
levels >180 mg/dL (>430 nmol/L) may have an increased lifetime risk of ASCVD
similar to that of people with heterozygous FH (HeFH). Because about 90% of a
person’s Lp(a) level is inherited, extremely elevated Lp(a) may represent a new
inherited lipid disorder that is associated with extremely high lifetime risk of
ASCVD and is two-fold more prevalent than HeFH.77 However, this study77 and
another based on the Heart Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascular Events (HPS2-THRIVE) trial78 have shown that large
absolute changes in Lp(a) may be needed to produce a clinically meaningful
reduction in the risk of ASCVD events.

5.4 LABORATORY MEASUREMENT OF LIPIDS AND LIPOPROTEINS

Measurement of lipids and lipoproteins is used to estimate the risk of ASCVD and
guide therapeutic decision-making. Quantification of plasma lipids can be
performed on whole plasma and quantification of lipoproteins can be achieved by
measuring their protein component. Operationally, lipoproteins are classified
based on their hydrated density (see Table 6).

5.4.1 LIPOPROTEIN MEASUREMENT

Given the central causal role of ApoB-containing lipoproteins in the initiation
and progression of atherosclerosis, direct measurement of the circulating
concentration of atherogenic ApoB-containing lipoproteins to both estimate risk
and guide treatment decisions would be ideal. Because all ApoB-containing
lipoproteins—including VLDL, TG-rich remnant particles, and LDL—contain a single
ApoB molecule, quantitation of ApoB directly estimates the number of atherogenic
particles in plasma.

Standardized, automated, accurate, and inexpensive methods to measure ApoB are
available. Fasting is not required because even in the post-prandial state,
ApoB48-containing chylomicrons typically represent <1% of the total
concentration of circulating ApoB-containing lipoproteins. Furthermore, the
analytical performances of ApoB measurement methods are superior to the
measurement or calculation of LDL-C and non-HDL-C.79

5.4.2 LIPID MEASUREMENTS

In clinical practice, the concentration of plasma lipoproteins is not usually
measured directly but is instead estimated by measuring their cholesterol
content. TC in humans is distributed primarily among three major lipoprotein
classes: VLDL, LDL, and HDL. Smaller amounts of cholesterol are also contained
in two minor lipoprotein classes: IDL and Lp(a). A standard serum lipid profile
measures the concentration of TC and HDL-C, as well as TG. With these values,
the LDL-C concentration can be estimated.

Plasma LDL-C can be measured directly using enzymatic techniques or preparative
ultracentrifugation, but in clinical medicine it is most often calculated using
the Friedewald formula:

> LDL-C = TC − HDL-C − (TG/2.2) in mmol/L
>
> or
>
> LDL-C = TC − HDL-C − (TG/5) in mg/dL

Although convenient, the Friedewald calculated value of LDL-C has several
well-established limitations: (i) methodological errors may accumulate since the
formula necessitates three separate analyses of TC, TGs, and HDL-C; and (ii) a
constant cholesterol/TG ratio in VLDL is assumed. With high TG values (>4.5
mmol/L or >400 mg/dL) the formula cannot be used. This should especially be
considered in non-fasting samples.

To overcome the problems associated with calculated LDL-C, direct enzymatic
methods for the measurement of LDL-C have been developed. These methods are
commercially available as ready to use tools for automatic analysis. The
definition of LDL-C by the Friedewald equation and by direct measurement is the
same: non-HDL-C – VLDL-C, representing the sum of the cholesterol carried by the
biochemically defined LDL, IDL, and Lp(a) subfractions.

For the general population, calculated LDL-C and direct LDL-C show very strong
correlations.80–83 However, calculated LDL-C has been found to underestimate
LDL-C at concentrations of TG ≥2 mmol/L (177 mg/dL).81,82 Equally, at very low
levels of LDL-C, calculated LDL-C may be misleading, especially in the presence
of high TG.81,84–86 To avoid some of the problems with the Friedewald formula, a
number of modifications for the calculation of LDL-C have been suggested, but it
remains to be proved whether these modifications are superior to Friedewald’s
formula for the estimation of CV risk.81,85–87 It is important to note that
direct LDL-C measurements also have limitations, including systematic bias and
inaccuracy in patients with dyslipidaemia, especially for high TG levels.88–90

As an alternative calculated LDL-C, non-HDL-C can be calculated as TC – HDL-C
and is a measure of the TC carried by all atherogenic ApoB-containing
lipoproteins, including TG-rich particles in VLDL and their remnants.100

Several methods for the determination of Lp(a) are available. The complex
molecular structure of Lp(a) and the variation in size of Apo(a) has been a
challenge in the development of analytical methods for Lp(a). Available methods
are, to a varying degree, influenced by the Apo(a) isoform.91 Furthermore, the
concentration of Lp(a) is reported as either a molar concentration (nmol/L) or
as a mass (mg/dL) by the various assays, and conversion between molar and mass
concentrations has been found to be both size- and concentration-dependent.91–93
Therefore, standardization between assays is needed to establish a reliable and
reproducible method for the quantification of Lp(a) mass or particle number.92

5.4.3 FASTING OR NON-FASTING?

Traditionally, blood sampling for lipid analyses has been recommended in the
fasting state. Recent systematic studies comparing fasting and non-fasting
samples have suggested that the difference is small for most lipid
parameters.85,94–100 Non-fasting sampling has been used in large
population-based studies.100 In most studies, non-fasting samples display a
higher TG level of ∼0.3 mmol/L (27 mg/dL).100,101 On average, and for most
individuals, this increment will be of no clinical significance. Indeed, a
number of guidelines recommend non-fasting sampling.100,102,103

For general risk screening, non-fasting samples seem to have at least the same
prognostic value as fasting samples.104 The practical advantages of non-fasting
samples, including better patient acceptability, outweigh the potential
imprecision in some patients, although the determination of some key analytes,
such as fasting glucose, may be compromised. Furthermore, even if non-fasting
sampling can be used in most cases, in patients with metabolic syndrome (MetS),
DM, or hypertriglyceridaemia (HTG), calculated LDL-C should be interpreted with
caution.

5.5 RECOMMENDATIONS FOR MEASURING LIPIDS AND LIPOPROTEINS TO ESTIMATE RISK OF
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Measurement of plasma TC is needed to calculate risk using SCORE, while the
inclusion of plasma HDL-C level can improve risk estimation using the online
SCORE calculator. Therefore, both TC and HDL-C should be measured to estimate a
person’s risk of ASCVD using SCORE, or one of the other risk calculators (almost
all of which also include measurements of TC and HDL-C).

Plasma LDL-C should be measured to estimate the risk of ASCVD that can be
modified with LDL-C-lowering therapies, and to identify whether markedly
elevated LDL-C levels are present that may suggest a lifetime high-risk of ASCVD
due to lifelong cumulative exposure to high levels of atherogenic lipoproteins,
such as in FH. Plasma LDL-C can be either calculated or measured directly.

Plasma TG should be assessed to identify people who may have a greater
modifiable risk of ASCVD than is reflected by LDL-C, due to the presence of an
increased concentration of atherogenic ApoB-containing TG-rich lipoproteins and
their remnants, and to identify people in whom calculated and directly measured
LDL-C may underestimate the risk of ASCVD by underestimating either the
concentration of circulating LDL particles or the cholesterol content carried by
those particles, such as those with very low levels of LDL. This may be
especially relevant in patients with DM or MetS.

In general, LDL-C, non-HDL-C, and ApoB concentrations are very highly
correlated. As a result, under most circumstances, they provide very similar
information about ASCVD risk.45,105–108 However, under certain
circumstances—including among people with elevated TG levels, DM, obesity, or
very low achieved LDL-C levels—the calculated or directly measured LDL-C level
may underestimate both the total concentration of cholesterol carried by LDL
and, more importantly, underestimate the total concentration of ApoB-containing
lipoproteins, thus underestimating the risk of ASCVD. In around 20% of patients
there may be discordance between measured LDL-C and ApoB levels.85,109

Considering the potential inaccuracy of LDL-C in dyslipidaemia, among patients
with DM or high TG levels, and in patients with very low LDL-C levels,
measurement of both ApoB and non-HDL-C is recommended as part of routine lipid
analysis for risk evaluation in patients with elevated plasma TGs. Because ApoB
provides an accurate estimate of the total concentration of atherogenic
particles under all circumstances, it is the preferred measurement to further
refine the estimate of ASCVD risk that is modifiable by lipid-lowering therapy.

Lp(a) has a similar structure to plasminogen and binds to the plasminogen
receptor, leading to increased thrombosis (pro-thrombotic factor). Measurement
of Lp(a) should be considered at least once in each person’s lifetime, if
available, to identify people who have inherited an extremely elevated level of
Lp(a) ≥180 mg/dL (≥430 nmol/L) and therefore have a very high lifetime risk of
ASCVD that is approximately equivalent to the risk associated with HeFH. In
addition, this strategy can identify people with less-extreme Lp(a) elevations
who may be at a higher risk of ASCVD, which is not reflected by the SCORE
system, or by other lipid or lipoprotein measurements. Measurement of Lp(a) has
been shown to provide clinically significant improved risk reclassification
under certain conditions, and therefore should be considered in patients who
have an estimated 10-year risk of ASCVD that is close to the threshold between
high and moderate risk.110–112

Recommendations for measuring lipids and lipoproteins to estimate the risk of
ASCVD are summarized below.

Recommendations for lipid analyses for cardiovascular disease risk estimation

Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CV =
cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; HDL-C =
high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein
cholesterol; Lp(a) = lipoprotein(a); SCORE = Systematic Coronary Risk
Estimation; TC = total cholesterol; TG = triglyceride.

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Recommendations for lipid analyses for cardiovascular disease risk estimation

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6 TREATMENT TARGETS AND GOALS

In previous EAS/ESC Guidelines for the management of dyslipidaemias1,113 and
other major guidelines on the treatment of blood cholesterol to reduce
atherosclerotic CV risk in adults,40,114 the importance of LDL-C lowering to
prevent ASCVD is strongly emphasized. The European Task Force felt that limiting
the current knowledge on CV prevention only to results from RCTs reduces the
exploitation of the potential that is available for the prevention of ASCVD. It
is the concordance of the conclusions from many different approaches (from basic
science, clinical observations, genetics, epidemiology, RCTs, etc.) that
contributes to the understanding of the causes of ASCVD and to the potential of
prevention. The Task Force is aware of the limitations of some of the sources of
evidence and accepts that RCTs have not examined different LDL-C goals
systematically, but felt that it was appropriate to look at the totality of the
evidence. Particular consideration was given to results from meta-analyses
confirming the dose-dependent reduction in ASCVD with LDL-C-lowering agents; the
greater the absolute LDL-C reduction, the greater the CV risk
reduction.35,36,50,115 The benefits related to LDL-C reduction are not specific
for statin therapy.33 No level of LDL-C below which benefit ceases or harm
occurs has been defined.

There is considerable individual variability in the LDL-C response to dietary
and drug treatments,31 which is traditionally taken to support a tailored
approach to management. Total CV risk reduction should be individualized, and
this can be more specific if goals are defined. The use of goals can also aid
patient–doctor communication. It is judged that a goal approach may facilitate
adherence to treatment, although this consensus opinion has not been fully
tested. For all these reasons, the European Task Force retains a goal approach
to lipid management and treatment goals are tailored to the total CV risk level.
There is also evidence suggesting that lowering of LDL-C beyond the goals that
were set in the previous EAS/ESC Guidelines is associated with fewer ASCVD
events.34,116,117 Therefore, it seems appropriate to reduce LDL-C to as low a
level as possible, at least in patients at very high CV risk, and for this
reason a minimum 50% reduction is suggested for LDL reduction, together with
reaching the tailored goal.

The lipid goals are part of a comprehensive CV risk reduction strategy and are
summarized in Table 7. The rationales for the non-lipid targets are given in the
2016 ESC Joint Prevention Guidelines.10

Table 7

Treatment targets and goals for cardiovascular disease prevention

Smoking No exposure to tobacco in any form. Diet Healthy diet low in saturated
fat with a focus on wholegrain products, vegetables, fruit, and fish. Physical
activity 3.5–7 h moderately vigorous physical activity per week or 30–60 min
most days. Body weight BMI 20–25 kg/m2, and waist circumference <94 cm (men) and
<80 cm (women). Blood pressure <140/90 mmHg.a LDL-C

* Very-high risk in primary or secondary prevention:

* A therapeutic regimen that achieves ≥50% LDL-C reduction from baselineb and
an LDL-C goal of <1.4 mmol/L (<55 mg/dL).

* No current statin use: this is likely to require high-intensity LDL-lowering
therapy.

* Current LDL-lowering treatment: an increased treatment intensity is required.

* High risk: A therapeutic regimen that achieves ≥50% LDL-C reduction from
baselineb and an LDL-C goal of <1.8 mmol/L (<70 mg/dL).

* Moderate risk:

* A goal of <2.6 mmol/L (<100 mg/dL).

* Low risk:

* A goal of <3.0 mmol/L (<116 mg/dL).

Non-HDL-C Non-HDL-C secondary goals are <2.2, 2.6, and 3.4 mmol/L (<85, 100,
and 130 mg/dL) for very-high-, high-, and moderate-risk people,
respectively. ApoB ApoB secondary goals are <65, 80, and 100 mg/dL for
very-high-, high-, and moderate-risk people, respectively. Triglycerides No
goal, but <1.7 mmol/L (<150 mg/dL) indicates lower risk and higher levels
indicate a need to look for other risk factors. Diabetes HbA1c: <7% (<53
mmol/mol).

* Very-high risk in primary or secondary prevention:

* A therapeutic regimen that achieves ≥50% LDL-C reduction from baselineb and
an LDL-C goal of <1.4 mmol/L (<55 mg/dL).

* No current statin use: this is likely to require high-intensity LDL-lowering
therapy.

* Current LDL-lowering treatment: an increased treatment intensity is required.

* High risk: A therapeutic regimen that achieves ≥50% LDL-C reduction from
baselineb and an LDL-C goal of <1.8 mmol/L (<70 mg/dL).

* Moderate risk:

* A goal of <2.6 mmol/L (<100 mg/dL).

* Low risk:

* A goal of <3.0 mmol/L (<116 mg/dL).

Apo = apolipoprotein; BMI = body mass index; HbA1c = glycated haemoglobin; HDL-C
= high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein
cholesterol.

Lower treatment targets are recommended for most treated hypertensive patients,
provided that the treatment is well tolerated.118

The term ‘baseline’ refers to the LDL-C level in a person not taking any
lipid-lowering medication, or to the extrapolated baseline value for those who
are on current treatment.

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Table 7

Treatment targets and goals for cardiovascular disease prevention

* Very-high risk in primary or secondary prevention:

* A therapeutic regimen that achieves ≥50% LDL-C reduction from baselineb and
an LDL-C goal of <1.4 mmol/L (<55 mg/dL).

* No current statin use: this is likely to require high-intensity LDL-lowering
therapy.

* Current LDL-lowering treatment: an increased treatment intensity is required.

* High risk: A therapeutic regimen that achieves ≥50% LDL-C reduction from
baselineb and an LDL-C goal of <1.8 mmol/L (<70 mg/dL).

* Moderate risk:

* A goal of <2.6 mmol/L (<100 mg/dL).

* Low risk:

* A goal of <3.0 mmol/L (<116 mg/dL).

* Very-high risk in primary or secondary prevention:

* A therapeutic regimen that achieves ≥50% LDL-C reduction from baselineb and
an LDL-C goal of <1.4 mmol/L (<55 mg/dL).

* No current statin use: this is likely to require high-intensity LDL-lowering
therapy.

* Current LDL-lowering treatment: an increased treatment intensity is required.

* High risk: A therapeutic regimen that achieves ≥50% LDL-C reduction from
baselineb and an LDL-C goal of <1.8 mmol/L (<70 mg/dL).

* Moderate risk:

* A goal of <2.6 mmol/L (<100 mg/dL).

* Low risk:

* A goal of <3.0 mmol/L (<116 mg/dL).

Apo = apolipoprotein; BMI = body mass index; HbA1c = glycated haemoglobin; HDL-C
= high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein
cholesterol.

Lower treatment targets are recommended for most treated hypertensive patients,
provided that the treatment is well tolerated.118

The term ‘baseline’ refers to the LDL-C level in a person not taking any
lipid-lowering medication, or to the extrapolated baseline value for those who
are on current treatment.

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The targeted approach to lipid management is primarily aimed at reducing
atherosclerotic risk by substantially lowering LDL-C to levels that have been
achieved in recent large-scale trials of PCSK-9 inhibitors. Therefore, for
patients at very high CV risk, whether in secondary prevention or (rarely) in
primary prevention, LDL-C reduction of ≥50% from baseline and an LDL-C goal of
<1.4 mmol/L (<55 mg/dL) are recommended. For patients with ASCVD who experience
a second vascular event within 2 years (not necessarily of the same type as the
first event) while taking maximally tolerated statin-based therapy, an LDL-C
goal <1.0 mmol/L (<40 mg/dL) may be considered.119,120 For people at high CV
risk, an LDL-C reduction of ≥50% from baseline and an LDL-C goal <1.8 mmol/L
(<70 mg/dL) are recommended. In patients at moderate CV risk, an LDL-C goal <2.6
mmol/L (<100 mg/dL) should be considered, while for low-risk individuals a goal
of <3.0 mmol/L (<116 mg/dL) may be considered (see Recommendations for treatment
goals for low-density lipoprotein cholesterol below and Supplementary Table 2).

Recommendations for treatment goals for low-density lipoprotein cholesterol

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol.

Class of recommendation.

Level of evidence.

For definitions see Table 4.

The term ‘baseline’ refers to the LDL-C level in a person not taking any
LDL-C-lowering medication. In people who are taking LDL-C-lowering
medication(s), the projected baseline (untreated) LDL-C levels should be
estimated, based on the average LDL-C-lowering efficacy of the given medication
or combination of medications.

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Recommendations for treatment goals for low-density lipoprotein cholesterol

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol.

Class of recommendation.

Level of evidence.

For definitions see Table 4.

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Secondary goals have also been defined by inference for non-HDL-C and for ApoB;
they receive a moderate grading, as they have not been extensively studied in
RCTs. The specific goal for non-HDL-C should be 0.8 mmol/L (30 mg/dL) higher
than the corresponding LDL-C goal; the adjustment of lipid-lowering therapy in
accordance with these secondary goals may be considered in patients at very high
CV risk after achievement of an LDL-C goal, although the clinical advantages of
this approach with respect to outcomes remain to be addressed. When secondary
targets are used the recommendations are: (i) non-HDL-C <2.2 mmol/L (<85 mg/dL),
<2.6 mmol/L (<100 mg/dL), and <3.4 mmol/L (<130 mg/dL) in people at very high,
high, and moderate CV risk, respectively;121–123 and (ii) ApoB <65 mg/dL, <80
mg/dL, and <100 mg/dL in very-high, high, and moderate total CV risk,
respectively.121,123,124

To date, no specific goals for HDL-C or TG levels have been determined in
clinical trials, although increases in HDL-C predict atherosclerosis regression,
and low HDL-C is associated with excess events and mortality in coronary artery
disease (CAD) patients, even at low LDL levels. Clinicians should use clinical
judgment when considering further treatment intensification in patients at high
or very high total CV risk.

7 LIFESTYLE MODIFICATIONS TO IMPROVE THE PLASMA LIPID PROFILE

The pivotal role of nutrition in the prevention of ASCVD has been extensively
reviewed.125–129 Dietary factors influence the development of CVD either
directly or through their action on traditional risk factors, such as plasma
lipids, BP, or glucose levels.

Convincing evidence of the causal association between diet and ASCVD risk is,
nevertheless, available indirectly from randomized ‘metabolic ward’ studies
showing that high saturated fat intake causes increased LDL-C concentrations,
and from cohort studies, genetic epidemiological studies, and randomized trials
showing that higher LDL-C levels cause ASCVD.

The lack of concordance between studies is due both to methodological problems
(particularly inadequate sample sizes or short study durations) and the
difficulties of evaluating the impact of a single dietary factor independently
of any other changes in the diet.130 In fact, as foods are mixtures of different
nutrients and other components, it is not appropriate to attribute the health
effects of a food to only one of its components. Moreover, if energy intake must
be kept constant, eating less of one macronutrient implies necessarily eating
more of others. The quality of the replacement (for instance, unsaturated fat
vs. highly refined grains) can influence the effect observed, significantly
modifying the impact on health of the nutrient replaced. These limitations
suggest caution in interpreting the results of RCTs or even meta-analyses of
RCTs in relation to the effect of a single dietary change on ASCVD.130

To overcome, at least in part, these problems, in recent years nutrition
research has focused on the relationship between ASCVD on the one hand, and
foods and dietary patterns—rather than single nutrients—on the other. Consistent
evidence from epidemiological studies indicates that higher consumption of
fruit, non-starchy vegetables, nuts, legumes, fish, vegetable oils, yoghurt, and
wholegrains, along with a lower intake of red and processed meats, foods higher
in refined carbohydrates, and salt, is associated with a lower incidence of CV
events.131 Moreover, it indicates that the replacement of animal fats, including
dairy fat, with vegetable sources of fats and polyunsaturated fatty acids
(PUFAs) may decrease the risk of CVD.132

Dietary patterns that have been more extensively evaluated are the Dietary
Approaches to Stop Hypertension (DASH) diet—particularly in relation to BP
control—and the Mediterranean diet; both have proved to be effective in reducing
CV risk factors and, possibly, to contribute to ASCVD prevention.133 The most
relevant difference between the Mediterranean and the DASH diet is the emphasis
of the former on extra-virgin olive oil. The Mediterranean diet is associated
with a reduced incidence of CV and other non-communicable diseases in
epidemiological studies,134,135 and has been proved in RCTs to be effective in
reducing CV events in primary and secondary prevention.136 In particular, the
Prevención con Dieta Mediterránea (PREDIMED) trial indicated that participants
allocated to a Mediterranean-type diet, supplemented with extra-virgin olive oil
or nuts, had a significantly lower (around 30%) incidence of major CV events
compared with those who were on a low-fat diet.137

In summary, despite the results of PREDIMED and a few other intervention studies
with ASCVD endpoints that support a healthy lifestyle for ASCVD prevention, RCTs
cannot represent the sole grounds on which dietary recommendations should rely.
They also need to be based on the combination of large observational cohort
studies and relatively short-term randomized trials having intermediate risk
factors (such as blood lipids) as outcomes.

Table 8 summarizes the currently available evidence on the influences of
lifestyle changes and functional foods on lipoproteins, indicating the
magnitudes of the effects and the levels of evidence in relation to the impacts
on the specific lipoprotein class; for the reasons outlined above, the levels of
evidence are not based on RCTs with ASCVD endpoints. Moreover, within the
Guidelines on the management of dyslipidaemias, information on the potential to
improve plasma lipoprotein profiles by dietary means is clinically relevant,
even in the absence of a clear demonstration of CV benefits.

Table 8

Impact of specific lifestyle changes on lipid levels

The magnitude of the effect (+++ = >10%, ++ = 5–10%, + = <5%) and the level of
evidence refer to the impact of each dietary modification on plasma levels of a
specific lipoprotein class.

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein
cholesterol; TC = total cholesterol; TG = triglyceride.

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Table 8

Impact of specific lifestyle changes on lipid levels

The magnitude of the effect (+++ = >10%, ++ = 5–10%, + = <5%) and the level of
evidence refer to the impact of each dietary modification on plasma levels of a
specific lipoprotein class.

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein
cholesterol; TC = total cholesterol; TG = triglyceride.

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7.1 INFLUENCE OF LIFESTYLE ON TOTAL CHOLESTEROL AND LOW-DENSITY LIPOPROTEIN
CHOLESTEROL LEVELS

Saturated fatty acids (SFAs) are the dietary factor with the greatest impact on
LDL-C levels (0.02–0.04 mmol/L or 0.8–1.6 mg/dL of LDL-C increase for every
additional 1% energy coming from saturated fat).164 Quantitatively, dietary
trans fatty acids have a similar elevating effect on LDL-C to that of SFAs;
however, while SFAs increase HDL-C levels, trans fats decrease them.137 Trans
unsaturated fatty acids can be found in limited amounts (usually <5% of total
fat) in dairy products and in meats from ruminants. ‘Partially hydrogenated
fatty acids’ of industrial origin represent the major source of trans fatty
acids in the diet; the average consumption of trans fatty acids ranges from
0.2–6.5% of the total energy intake in different populations.165 Unsaturated
fat-rich oils from safflower, sunflower, rapeseed, flaxseed, corn, olives, or
soybean were shown to reduce LDL-C levels (−0.42 to −0.20 mmol/L) when used in
substitution of SFA-rich foods like butter or lard.166 The effects of
carbohydrate consumption on LDL-C are described in section 7.4.3.

Body weight reduction also influences TC and LDL-C levels, but the magnitude of
the effect is small: in obese people, a decrease in LDL-C concentration of 0.2
mmol/L (8 mg/dL) is observed for every 10 kg of weight loss.147,167 The
reduction of LDL-C levels induced by regular physical exercise is even
smaller.151,168 The benefits of weight reduction and physical exercise on the CV
risk profile likely impact on other risk factors, especially hypertension and
diabetes.

Table 9 summarizes the possible choices of foods to lower TC and LDL-C levels.
Given the cultural diversity of the European populations, they should be
translated into practical behaviours, considering local habits and
socio-economic factors.

Table 9

Food choices to lower low-density lipoprotein cholesterol and improve the
overall lipoprotein profile

. To be preferred . To be used in moderation . To be chosen occasionally in
limited amounts . Cereals Wholegrains Refined bread, rice, and pasta, biscuits,
corn flakes Pastries, muffins, pies, croissants Vegetables Raw and cooked
vegetables Potatoes Vegetables prepared in butter or cream Legumes Lentils,
beans, fava beans, peas, chickpeas, soybean Fruit Fresh or frozen fruit Dried
fruit, jelly, jam, canned fruit, sorbets, ice lollies/popsicles, fruit
juice Sweets and sweeteners Non-caloric sweeteners Sucrose, honey, chocolate,
sweets/candies Cakes, ice creams, fructose, soft drinks Meat and fish Lean and
oily fish, poultry without skin Lean cuts of beef, lamb, pork, and veal,
seafood, shellfish Sausages, salami, bacon, spare ribs, hot dogs, organ
meats Dairy food and eggs Skimmed milk and yoghurt Low-fat milk, low-fat cheese
and other milk products, eggs Regular cheese, cream, whole milk and
yoghurt Cooking fat and dressings Vinegar, mustard, fat-free dressings Olive
oil, non-tropical vegetable oils, soft margarines, salad dressing, mayonnaise,
ketchup Trans fats and hard margarines (better to avoid them), palm and coconut
oils, butter, lard, bacon fat Nuts/seeds All, unsalted (except
coconut) Coconut Cooking procedures Grilling, boiling, steaming Stir-frying,
roasting Frying

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Table 9

Food choices to lower low-density lipoprotein cholesterol and improve the
overall lipoprotein profile

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7.2 INFLUENCE OF LIFESTYLE ON TRIGLYCERIDE LEVELS

Weight reduction improves insulin sensitivity and decreases TG levels. Regular
physical exercise reduces plasma TG levels over and above the effect of weight
reduction.151,168,169 Alcohol intake has a major impact on TG levels,
particularly in individuals with HTG.153,170 The detrimental effects of a
high-carbohydrate diet on TGs occur mainly when refined carbohydrate-rich foods
are consumed, while they are much less prominent if the diet is based largely on
fibre-rich, low-glycaemic index foods. This applies particularly to people with
DM or MetS.171,172

Habitual consumption of significant amounts (>10% energy) of dietary fructose
contributes to TG elevation, particularly in people with HTG or abdominal
obesity. These effects are dose-dependent; with a habitual fructose consumption
between 15–20% of total energy intake, plasma TG increases by as much as 30–40%.
Sucrose, a disaccharide containing glucose and fructose, represents an important
source of fructose in the diet.159,173,174

7.3 INFLUENCE OF LIFESTYLE ON HIGH-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS

Weight reduction increases HDL-C levels; a 0.01 mmol/L (0.4 mg/dL) increase is
observed for every kilogram decrease in body weight when weight reduction has
stabilized. Aerobic physical activity, such as 25–30 km of brisk walking per
week (or any equivalent activity), may increase HDL-C levels by 0.08–0.15 mmol/L
(3.1–6 mg/dL).169 Smoking cessation may also contribute to HDL-C elevation,
provided that weight gain is prevented.163

7.4 LIFESTYLE RECOMMENDATIONS TO IMPROVE THE PLASMA LIPID PROFILE

LDL-C lowering represents the primary target for reducing CV risk and therefore
deserves special emphasis in the evaluation of lifestyle measures. The diet
recommended to the general population, and particularly to people at increased
CV risk, may also be able to modify plasma TG and HDL-C levels (Table 9). This
section focuses on dietary and other lifestyle factors that may be implemented
to improve the overall lipoprotein profile.

7.4.1 BODY WEIGHT AND PHYSICAL ACTIVITY

Since overweight, obesity, and—in particular—abdominal adiposity often
contribute to dyslipidaemia, caloric intake should be reduced and energy
expenditure increased in those with excessive weight and/or abdominal adiposity.

In the case of excess weight, body weight reduction, even if modest (5–10% of
basal body weight), improves lipid abnormalities and favourably affects the
other CV risk factors often present in dyslipidaemic individuals.148 While the
beneficial effects of weight reduction on metabolic and surrogate markers have
been demonstrated, the benefits of weight loss on mortality and CV outcome are
less clear.175

Weight reduction can be achieved by decreasing the consumption of energy-dense
foods, inducing a caloric deficit of 300–500 kcal/day. The intervention should
combine diet and exercise; this approach also leads to the greatest improvement
in physical performance and quality of life, and mitigates reductions in muscle
and bone mass, particularly in older people.176 It is always appropriate to
advise people with dyslipidaemia to engage in regular physical exercise of
moderate intensity for ≥30 min/day, even if they are not overweight.168

7.4.2 DIETARY FAT

Avoiding any consumption of trans fat is a key measure of the dietary prevention
of CVD. The trans fatty acids produced in the partial hydrogenation of vegetable
oils account for 80% of total intake. Thanks to efforts made in different parts
of the world, the intake of trans fatty acids has decreased substantially over
the past 10–15 years.

As for saturated fat, its consumption should be <10% of the total caloric intake
and should be further reduced (<7% of energy) in the presence of
hypercholesterolaemia. For most individuals, a wide range of total fat intakes
is acceptable, and will depend upon individual preferences and characteristics.
However, fat intakes >35–40% of calories are generally associated with increased
intakes of both saturated fat and calories. Conversely, low intakes of fats and
oils increase the risk of inadequate intakes of vitamin E and of essential fatty
acids, and may contribute to a reduction of HDL-C.164

Fat intake should predominantly come from sources of monounsaturated fatty
acids, including both n-6 and n-3 PUFAs. Not enough data are available to make a
recommendation regarding the optimal n-3:n-6 fatty acid ratio.177,178 The
cholesterol intake in the diet should be reduced (<300 mg/day), particularly in
people with high plasma cholesterol levels.

7.4.3 DIETARY CARBOHYDRATE AND FIBRE

Dietary carbohydrate has a ‘neutral’ effect on LDL-C, although excessive
consumption is represented by untoward effects on plasma TGs and HDL-C
levels.164 Dietary fibre (particularly of the soluble type)—which is present in
legumes, fruits, vegetables, and wholegrain cereals (e.g. oats and barley)—has a
hypocholesterolaemic effect and represents a good dietary substitute for
saturated fat to maximize the effects of the diet on LDL-C levels, and to
minimize the untoward effects of a high-carbohydrate diet on other
lipoproteins.140,179

Carbohydrate intake should range between 45–55% of total energy intake, since
both higher and lower percentages of carbohydrate diets are associated with
increased mortality.180,181 A fat-modified diet that provides 25–40 g per day of
total dietary fibre, including ≥7–13 g of soluble fibre, is well tolerated,
effective, and recommended for plasma lipid control; conversely, there is no
justification for the recommendation of very low-carbohydrate diets.182

Intake of added sugar should not exceed 10% of total energy (in addition to the
amount present in natural foods such as fruits and dairy products); more
restrictive advice concerning sugars may be useful for those needing to lose
weight or with high plasma TG values, MetS, or DM. Soft drinks should be used
with moderation by the general population, and should be drastically limited in
those individuals with elevated TG values or visceral adiposity.158,159,174 The
Prospective Urban Rural Epidemiology (PURE) study was a large, epidemiological
cohort study of 135 335 individuals enrolled in 18 countries with food frequency
questionnaires recorded. Total fat and types of fat were not associated with
CVD, MI, or CVD mortality, whereas saturated fat had an inverse association with
stroke.181 However, a meta-analysis of epidemiological studies including the
PURE study showed a U-shaped relationship between carbohydrate intake and
mortality: diets associated with the highest mortality rate had carbohydrate
intakes >70% and <40% of energy, with minimal risk observed when carbohydrate
intake was between 45–55% of total energy intake.180

7.4.4 ALCOHOL

Moderate alcohol consumption [≤10 g/day (1 unit) for men and women] is
acceptable for those who drink alcoholic beverages, if TG levels are not
elevated.183,184

7.4.5 SMOKING

Smoking cessation has clear benefits regarding overall CV risk, and specifically
on HDL-C levels.163

7.5 DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS FOR THE TREATMENT OF DYSLIPIDAEMIAS

Nutritional evaluation of functional foods includes not only the search for
clinical evidence of beneficial effects relevant to improved health or the
reduction of disease risk, but also the demonstration of good tolerability.
Overall, the available evidence on functional foods so far identified in this
field is incomplete; the major gap is an absence of diet-based intervention
trials of enough duration to be relevant for the natural history of
dyslipidaemia and CVD.

7.5.1 PHYTOSTEROLS

The principal phytosterols are sitosterol, campesterol, and stigmasterol; they
occur naturally in vegetable oils and in smaller amounts in vegetables, fresh
fruits, nuts, grains, and legumes. The dietary intake of plant sterols ranges
between an average of 250 mg/day in Northern Europe to ∼500 mg/day in
Mediterranean countries. Phytosterols compete with cholesterol for intestinal
absorption, thereby modulating TC levels.

Daily consumption of 2 g of phytosterols can effectively lower TC and LDL-C
levels by 7–10% in humans (with a certain degree of heterogeneity among
individuals), while it has little or no effect on HDL-C and TG levels.143
However, to date no studies have been performed on the subsequent effect on CVD.
Based on LDL-C lowering and the absence of adverse signals, functional foods
with plant sterols/stanols (≥2 g/day with the main meal) may be considered: (i)
in individuals with high cholesterol levels at intermediate or low global CV
risk who do not qualify for pharmacotherapy; (ii) as an adjunct to
pharmacological therapy in high- and very-high-risk patients who fail to achieve
LDL-C goals on statins or could not be treated with statins; and (iii) in adults
and children (aged >6 years) with FH, in line with current guidance.142

7.5.2 MONACOLIN AND RED YEAST RICE

Red yeast rice (RYR) is a source of fermented pigment that has been used in
China as a food colorant and flavour enhancer for centuries.
Hypocholesterolaemic effects of RYR are related to a statin-like
mechanism—inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase—of
monacolins, which represent the bioactive ingredient. Different commercial
preparations of RYR have different concentrations of monacolins, and lower TC
and LDL-C levels to variable extents, but the consumer is not able to make that
distinction.144,185 Moreover, the long-term safety of the regular consumption of
these products has not been fully documented and safety issues due to the
possible presence of contaminants in some preparations have been raised. Side
effects like those observed with statins have also been reported.

In the only available RCT in patients with ASCVD, a partially purified extract
of RYR reduced recurrent events by 45%.146 A clinically relevant
hypocholesterolaemic effect (up to a 20% reduction) has been observed with RYR
preparations providing an o.d. [once daily (omni die)] dose of 2.5–10 mg
monacolin K.145 Nutraceuticals containing purified RYR may be considered in
people with elevated plasma cholesterol concentrations who do not qualify for
treatment with statins in view of their global CV risk. However, there is a
clear need for better regulation of RYR supplements. Information regarding the
precise composition of these products, the quantities of their components, and
their purity should be implemented.185

7.5.3 DIETARY FIBRE

Available evidence consistently demonstrates a TC- and LDL-C-lowering effect of
β-glucan, a viscous fibre from oat and barley. Foods enriched with these fibres
or supplements are well tolerated, effective, and recommended for LDL-C
lowering.186 However, the dosage needed to achieve a clinically relevant
reduction in levels of LDL-C of 3–5% varies from 3–10 g per day according to the
specific type of fibre.187

7.5.4 SOY

The cholesterol-lowering effect of soy is generally attributed to its isoflavone
and phytoestrogen content, which decreases progressively with the increasing
degree of soybean processing. Soy protein has also been indicated as being able
to induce a modest LDL-C-lowering effect when replacing animal protein foods.
However, this was not confirmed when changes in other dietary components were
taken into account.187,188

7.5.5 POLICOSANOL AND BERBERINE

Policosanol is a natural mixture of long-chain aliphatic alcohols extracted
primarily from sugarcane wax.189 Studies show that policosanol from sugarcane,
rice or wheat germ has no significant effect on LDL-C, HDL-C, TG, ApoB, Lp(a),
homocysteine, high-sensitivity C-reactive protein, fibrinogen, or blood
coagulation factor levels.190

As for berberine, a recent meta-analysis evaluated its effects on plasma lipids
in humans.191 The comparative evaluation of berberine and lifestyle intervention
or placebo indicated that in the berberine group, LDL-C and plasma TG levels
were more effectively reduced than in the control group. However, due to the
lack of high-quality randomized clinical trials, the efficacy of berberine for
treating dyslipidaemia needs to be further validated. Moreover, the
bioavailability of the different berberine preparations is a matter of
debate.187

7.5.6 N-3 UNSATURATED FATTY ACIDS

Observational evidence indicates that consumption of fish (at least twice a
week) and vegetable foods rich in n-3 fatty acids (α-linoleic acid is present in
walnuts, some vegetables, and some seed oils) is associated with lower risk of
CV death and stroke, but has no major effects on plasma lipoprotein
metabolism.178,192 Pharmacological doses of long-chain n-3 fatty acids (2–3
g/day) reduce TG levels by about 30% and also reduce the post-prandial lipaemic
response, but a higher dosage may increase LDL-C levels. α-Linolenic acid is
less effective at altering TG levels.156,193 Recently, a significantly lower
risk of ischaemic events, including CV death, was observed in patients with
elevated TG levels despite the use of statins treated with 2 g of icosapent
ethyl b.i.d. [twice a day].194

Other features of a healthy diet contributing to CVD prevention are presented in
the Supplementary Data.

8 DRUGS FOR TREATMENT OF DYSLIPIDAEMIAS

8.1 STATINS

8.1.1 MECHANISM OF ACTION

Statins reduce the synthesis of cholesterol in the liver by competitively
inhibiting the enzyme HMG-CoA reductase, the rate-limiting step in cholesterol
biosynthesis. The reduction in intracellular cholesterol promotes increased LDL
receptor (LDLR) expression at the surface of the hepatocytes, which in turn
results in increased uptake of LDL from the blood, and decreased plasma
concentrations of LDL- and other ApoB-containing lipoproteins, including TG-rich
particles.

8.1.2 EFFECTS ON LIPIDS

8.1.2.1 LOW-DENSITY LIPOPROTEIN CHOLESTEROL.

The degree of LDL-C reduction is dose-dependent and varies between the different
statins. A high-intensity regimen is defined as the dose of a statin that, on
average, reduces LDL-C by ≥50%; moderate-intensity therapy is defined as the
dose expected to reduce LDL-C by 30–50%. Notably, there is considerable
interindividual variation in LDL-C reduction with the same dose of drug.31 Poor
responses to statin treatment in clinical studies are to some extent caused by
poor compliance, but may also be explained by genetic backgrounds.195,196
Interindividual variations in statin responses warrant monitoring of responses
on initiation of therapy.

Among patients who cannot tolerate the recommended intensity of a statin because
of adverse effects or those who do not reach their goal, the addition of a
non-statin lipid-modifying agent to a maximally tolerated statin is
recommended.197,198

8.1.2.2 TRIGLYCERIDES.

Statins usually reduce TG levels by 10–20% from baseline values.199 More potent
statins (atorvastatin, rosuvastatin, and pitavastatin) demonstrate robust
lowering of TG levels, especially at high doses and in patients with elevated
TGs (HTG), in whom the absolute risk, and therefore the absolute risk reduction,
is larger.

The mechanism of the TG-lowering effect has not been fully elucidated, but it
seems to be partly independent of the LDLR pathway. It may involve the
upregulation of VLDL uptake by hepatocytes, as well as a reduction of the
production rate of VLDLs; these effects seem to be dependent on pre-treatment
VLDL concentrations.200

8.1.2.3 HIGH-DENSITY LIPOPROTEIN CHOLESTEROL.

In a meta-analysis,201 elevations in HDL-C levels varied with dose among the
respective statins; such elevations ranged from 1–10%. However, given the marked
statin-mediated decrement in atherogenic ApoB-containing lipoproteins, the
extent to which the very modest effect on HDL-C levels might contribute to the
overall observed reductions in CV risk consistently observed in statin
intervention trials cannot reliably be disentangled.

8.1.2.4 LIPOPROTEIN(A).

Statins only marginally affect Lp(a) plasma levels. Previous studies have
reported either no effect on or an increase of Lp(a) levels after statin
treatment.202,203 The mechanisms by which statins raise oxidized phospholipids
on Lp(a) require further investigation.

8.1.3 OTHER EFFECTS OF STATINS

Although reduction of LDL-C levels is the major effect of statins, a number of
other, potentially important effects have been suggested (pleiotropic effects of
statins).204,205 Among such effects that are potentially relevant for the
prevention of CVD are the anti-inflammatory and antioxidant effects of statin
treatment. These effects have been shown in vitro and in experimental systems,
but their clinical relevance remains unproven.18,206

8.1.3.1 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY.

A large number of meta-analyses have been performed to analyse the effects of
statins in populations and in subgroups.34–36,38,51,207–214 In the Cholesterol
Treatment Trialists (CTT) meta-analysis of individual participant data (IPD)
from >170 000 participants in 26 RCTs of a statin vs. control or a more vs. less
intensive statin regimen,34 for each 1 mmol/L reduction in LDL-C, statin/more
statin reduced major vascular events (MI, CAD death, or any stroke or coronary
revascularization) by ∼22%, major coronary events by 23%, CAD death by 20%,
total stroke by 17%, and total mortality by 10% over 5 years. The proportional
effects (per mmol/L reduction in LDL-C) on major vascular events were similar in
all subgroups examined, so the absolute risk reduction was proportional to the
absolute baseline risk. The relative benefits were half as large in the first
year as compared with subsequent years. There was no increased risk for any
non-CV cause of death, including cancer, in those allocated statins. The
absolute benefit from statin treatment was lower in people in primary
prevention, who are typically at lower risk.36,38,214,215 In the CTT
meta-analysis of treatment in people with a low-risk of vascular disease,36 the
relative risk reduction of major vascular events per mmol/L reduction in LDL-C
was at least as large in low-risk individuals (i.e. in primary prevention). In
those without a history of vascular disease, statin therapy reduced the risk of
all-cause mortality by 9% per mmol/L reduction in LDL cholesterol. Similar
results were reported in a Cochrane review in 2013.213 The West of Scotland
Coronary Prevention Study (WOSCOPS) data were recently reanalysed, and
demonstrated that even people without DM and a 10 year predicted ASCVD risk of
<7.5% benefit from statin treatment. There was also a legacy effect with a
mortality benefit of 18% in all-cause death over 20 years.216 Statins are
effective for the prevention of ASCVD in the elderly, including those aged >75
years.217 Statins are not effective in a few specific groups, notably those with
heart failure (HF) or patients receiving haemodialysis.214,218–222

Current available evidence from meta-analyses suggests that the clinical benefit
of statin treatment is largely a class effect, driven by the absolute LDL-C
reduction; therefore, the type of statin used should reflect the treatment goals
for a given patient.

The following scheme may be proposed.

* Evaluate the total CV risk of the individual.

* Determine the treatment goals (depending on current risk).

* Involve the patient in decisions on CV risk management.

* Choose a statin regimen and, where necessary, additional treatments (e.g.
ezetimibe or PCSK9 inhibitors) that can meet the treatment goals (per cent
and absolute value).

* Response to statin treatment is variable, therefore uptitration of the statin
dose may be required before additional LDL-lowering treatments are started.

These are general criteria for the choice of drug. Factors such as the clinical
condition of the patient, concomitant medications, drug tolerability, local
treatment tradition, and drug cost will play major roles in determining the
final choice of drug and dose.

Furthermore, the effects of statins on a number of other clinical conditions
have been evaluated. For cancer, a meta-analysis of IPD from randomized trials
has shown that statins do not have any significant effect on cancer, at least
over a period of ∼5 years.223 Other conditions, such as dementia,224 hepatic
steatosis,225 venous thromboembolism,226 atrial fibrillation,227,228 and
polycystic ovary syndrome229 have also been studied, and no effect of statins on
these conditions has been reliably demonstrated.

The suggested effect on Alzheimer's disease was recently reviewed in a Cochrane
analysis reporting no conclusive effect from statins.230 Furthermore,
neurocognitive functions were extensively investigated in the Evaluating PCSK9
Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk
Subjects (EBBINGHAUS) study231 and no excess risk was observed among patients on
a statin regimen randomized to a PCSK9 mAb.

8.1.4 ADVERSE EFFECTS AND INTERACTIONS OF STATINS

Statins differ in their absorption, bioavailability, plasma protein binding,
excretion, and lipophilicity. Evening administration is usually recommended.
Lovastatin and simvastatin are prodrugs, whereas the other available statins are
administered in their active form. Their bioavailability is relatively low,
owing to a first-pass effect in the liver, and many statins undergo significant
hepatic metabolism via cytochrome P450 (CYP) isoenzymes, except pravastatin,
rosuvastatin, and pitavastatin. These enzymes are expressed mainly in the liver
and gut wall. Although statins are generally very well tolerated, they do have
some specific adverse effects on muscle, glucose haemostasis, and haemorrhagic
stroke. However, there is also widespread misinformation about potential adverse
effects, as reviewed recently.232,233

8.1.4.1 ADVERSE EFFECTS ON MUSCLE.

Myopathy is the most clinically relevant adverse effect of statins. Among the
risk factors for myopathy, it is particularly important that interaction with
concomitant drug therapy is considered (see below). Rhabdomyolysis is the most
severe form of statin-induced muscle damage, characterized by severe muscular
pain, muscle necrosis, and myoglobinuria potentially leading to renal failure
and death. In rhabdomyolysis, creatine kinase (CK) levels are elevated by ≥10
times, and often ≥40 times, the upper limit of normal (ULN).234 The frequency of
rhabdomyolysis has been estimated to represent 1–3 cases/100 000
patient-years.235 Patients taking statin therapy frequently report muscle
symptoms [so-called ‘statin-associated muscle symptoms’ (SAMS)], and in
non-randomized, observational studies, statins are associated with muscular pain
and tenderness (myalgia) without CK elevation or major functional loss, with the
reported frequency of SAMS in such studies varying between 10–15% among
statin-treated individuals.236–238 However, in part because individuals in
observational studies are not blind to the treatment they are receiving, such
studies are unreliable when used to assess the adverse effects of statins.233 In
contrast, in blinded randomized trials of statins vs. placebo there is no, or
only a slightly, increased frequency of muscle symptoms in statin-allocated
groups.239,240 The Anglo-Scandinavian Cardiac Outcomes Trial – Lipid-Lowering
Arm (ASCOT-LLA) study addressed this issue by comparing the incidence of four
different adverse events, including muscle-related symptoms, during both the
blinded, placebo-controlled trial and its open-label extension study.238 They
concluded that a nocebo effect (i.e. one caused by negative expectations) may
partly explain the higher frequency of SAMS in observational studies compared
with in trials. Suggested practical management of muscular symptoms is shown in
Supplementary Figure 6.198,234,241 Several studies have shown a considerable
LDL-C-lowering effect of alternative dosing, such as every other day or twice a
week, with atorvastatin or rosuvastatin.242 Although no clinical endpoint trials
are available, this strategy should be considered in high-risk patients in whom
statin treatment with daily doses is not possible.

8.1.4.2 ADVERSE EFFECTS ON THE LIVER.

The activity of alanine aminotransferase (ALT) in plasma is commonly used to
assess hepatocellular damage. Mild elevation of ALT occurs in 0.5–2.0% of
patients on statin treatment, more commonly with potent statins or high doses.
The common definition of clinically relevant ALT elevation has been an increase
of three times the ULN on two consecutive occasions. Mild elevation of ALT has
not been shown to be associated with true hepatotoxicity or changes in liver
function. Progression to liver failure is exceedingly rare, therefore routine
monitoring of ALT during statin treatment is no longer recommended.243 Patients
with mild ALT elevation due to steatosis have been studied during statin
treatment and there is no indication that statins cause any worsening of liver
disease.244–246

8.1.4.3 INCREASED RISK OF NEW-ONSET DIABETES MELLITUS.

Patients on statin treatment have been shown to exhibit an increased risk of
dysglycaemia and development of type 2 diabetes mellitus (T2DM). Several studies
have shown that this is a consistent, dose-related effect.232 A minor, not
clinically relevant elevation of glycated haemoglobin (HbA1c) has also been
observed. The number needed to cause one case of diabetes has been estimated as
255 over 4 years of statin treatment.247 However, the risk is higher with the
more potent statins at high doses,248 and is also higher in the elderly, and in
the presence of other risk factors for diabetes such as overweight or insulin
resistance.249 Overall, the absolute reduction in the risk of CVD in high-risk
patients clearly outweighs the possible adverse effects of a small increase in
the incidence of diabetes.233 This effect is probably related to the mechanism
of action of statins, as Mendelian randomization studies have confirmed the
increased risk of DM in individuals with HMG-CoA reductase polymorphisms that
reduce cholesterol synthesis.250

8.1.4.4 INCREASED RISK OF HAEMORRHAGIC STROKE.

In observational studies, TC is negatively associated with haemorrhagic stroke,
and in the CTT meta-analysis, there was a 21% [95% confidence interval (CI)
5–41%; P=0.01] relative increase per mmol/L lower LDL cholesterol in
haemorrhagic stroke.34,251,252 However, other meta-analyses have yielded
conflicting findings and there is a need for further exploration of the risk of
haemorrhagic stroke in particular types of patients. Note, however, that the
overall benefit on other stroke subtypes greatly outweighs this small (and
uncertain) hazard.34,36

8.1.4.5 ADVERSE EFFECTS ON KIDNEY FUNCTION.

There is no clear evidence that statins have a clinically significant beneficial
or adverse effect on renal function.253 An increased frequency of proteinuria
has been reported for all statins, but has been analysed in more detail for
rosuvastatin. With a dose of 80 mg, a frequency of 12% was reported. With the
approved doses of <40 mg, the frequency is much lower and in line with the
frequency for other statins. The proteinuria induced by statins is of tubular
origin, usually transitory, and is believed to be due to reduced tubular
reabsorption and not to glomerular dysfunction.254,255 In clinical trials, the
frequency of proteinuria is generally low and, in most cases, is not higher than
for placebo.256

8.1.4.6 INTERACTIONS.

A number of important drug interactions with statins have been described that
may increase the risk of adverse effects. Inhibitors and inducers of enzymatic
pathways involved in statin metabolism are summarized in Table 10. All currently
available statins—except pravastatin, rosuvastatin, and pitavastatin—undergo
major hepatic metabolism via the CYPs. These isoenzymes are mainly expressed in
the liver and intestine. Pravastatin does not undergo metabolism through the CYP
system, but is metabolized by sulfation and conjugation. CYP3A4 isoenzymes are
the most abundant, but other isoenzymes such as CYP2C8, CYP2C9, CYP2C19, and
CYP2D6 are frequently involved in the metabolism of statins. Thus, other
pharmacological substrates of these CYPs may interfere with statin metabolism.
Conversely, statin therapy may interfere with the catabolism of other drugs that
are metabolized by the same enzymatic system.

Table 10

Drugs potentially interacting with statins metabolized by cytochrome P450 3A4
leading to increased risk of myopathy and rhabdomyolysis

Anti-infective agents . Calcium antagonists . Other
. Itraconazole Verapamil Ciclosporin Ketoconazole Diltiazem Danazol Posaconazole Amlodipine Amiodarone Erythromycin Ranolazine Clarithromycin Grapefruit
juice Telithromycin Nefazodone HIV protease inhibitors Gemfibrozil

Adapted from Egan and Colman,257 and Wiklund et al.258

HIV = human immunodeficiency virus.

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Table 10

Drugs potentially interacting with statins metabolized by cytochrome P450 3A4
leading to increased risk of myopathy and rhabdomyolysis

Adapted from Egan and Colman,257 and Wiklund et al.258

HIV = human immunodeficiency virus.

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Combination of statins with gemfibrozil enhances the risk of myopathy, and its
association with statins must be avoided. There is no or very little increased
risk for myopathy when combining statins with other fibrates, such as
fenofibrate, bezafibrate, or ciprofibrate.259,260

8.2 CHOLESTEROL ABSORPTION INHIBITORS

8.2.1 MECHANISM OF ACTION

Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol at the
level of the brush border of the intestine [by interacting with the Niemann-Pick
C1-like protein 1 (NPC1L1)] without affecting the absorption of fat-soluble
nutrients. By inhibiting cholesterol absorption, ezetimibe reduces the amount of
cholesterol delivered to the liver. In response to reduced cholesterol delivery,
the liver reacts by upregulating LDLR expression, which in turn leads to
increased clearance of LDL from the blood.

8.2.2 EFFECTS ON LIPIDS

In clinical studies, ezetimibe in monotherapy at 10 mg/day reduces LDL-C in
hypercholesterolaemic patients by 15–22% with relatively high interindividual
variation.261 A meta-analysis of RCTs that included over 2700 people showed an
18.5% reduction in LDL-C as compared with placebo.262 In addition, there was a
significant 3% increase in HDL-C, a significant 8% reduction in TGs, and a 13%
reduction in TC with ezetimibe as compared with placebo.

Ezetimibe added to ongoing statin therapy reduces LDL-C levels by an additional
21–27% compared with placebo in patients with hypercholesterolaemia with or
without established CHD. In statin-naïve patients, ezetimibe and statin
combination therapy has resulted in around a 15% greater reduction in LDL-C when
compared with the same statins and doses in monotherapy. In other studies, this
combination has also significantly improved reductions in LDL-C levels when
compared with doubling of the statin dose (13–20%), and after switching from
statin monotherapy to ezetimibe and statin combination therapy (11–15%).263

Co-administration of ezetimibe and bile acid sequestrants (colesevelam,
colestipol, or cholestyramine) has been reported to result in an additional
reduction of LDL-C levels by 10–20% when compared with the stable bile acid
sequestrant regimen alone.264 Co-administration of ezetimibe with PCSK9
inhibitors also results in an additional effect.265

8.2.3 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY

The efficacy of ezetimibe in association with simvastatin has been addressed in
people with aortic stenosis in the Simvastatin and Ezetimibe in Aortic Stenosis
(SEAS) trial,266 and in patients with CKD in the Study of Heart and Renal
Protection (SHARP) trial.222 In both the SEAS and SHARP trials, a reduction in
CV events was demonstrated in the simvastatin–ezetimibe arm vs. placebo.266,267

In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT), ezetimibe was added to simvastatin (40 mg) in patients after acute
coronary syndrome (ACS).33 A total of 18 144 patients were randomized to statin
or statin plus ezetimibe, and 5314 patients over 7 years experienced a CV event;
170 fewer events (32.7 vs. 34.7%) were recorded in the group taking simvastatin
plus ezetimibe (P=0.016). The average LDL-C during the study was 1.8 mmol/L (70
mg/dL) in the simvastatin group and 1.4 mmol/L (55 mg/dL) in patients taking
ezetimibe plus simvastatin. Also, ischaemic stroke was reduced by 21% in this
trial (P=0.008). There was no evidence of harm caused by ezetimibe or the
further LDL-C reduction. In this group of patients already treated with statins
to reach goals, the absolute CV benefit from added ezetimibe was small, although
significant and in line with the CTT expectations.268 Therefore, the study
supports the proposition that LDL-C lowering by means other than statins is
beneficial and safe. The beneficial effect of ezetimibe is also supported by
genetic studies of mutations in NPC1L1; naturally occurring mutations that
inactivate the protein were found to be associated with reduced plasma LDL-C and
reduced risk for CAD.55,269,270

Taken together with other studies,271 IMPROVE-IT supports the proposal that
ezetimibe should be used as second-line therapy in association with statins when
the therapeutic goal is not achieved at the maximal tolerated statin dose, or in
cases where a statin cannot be prescribed.272,273

8.2.4 ADVERSE EFFECTS AND INTERACTIONS

Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically
active ezetimibe glucuronide. The recommended dose of ezetimibe of 10 mg/day can
be administered in the morning or evening irrespective of food intake. There are
no clinically significant effects of age, sex, or race on ezetimibe
pharmacokinetics, and no dosage adjustment is necessary in patients with mild
hepatic impairment or mild-to-severe renal insufficiency. Life-threatening liver
failure with ezetimibe as monotherapy or in combination with statins is
extremely rare. The addition of ezetimibe to statin therapy does not appear to
increase the incidence of elevated CK levels beyond what is noted with statin
treatment alone.261

8.3 BILE ACID SEQUESTRANTS

8.3.1 MECHANISM OF ACTION

Bile acids are synthesized in the liver from cholesterol and are released into
the intestinal lumen, but most of the bile acid is returned to the liver from
the terminal ileum via active absorption. The two older bile acid sequestrants,
cholestyramine and colestipol, are both bile acid-binding exchange resins. The
synthetic drug colesevelam is also available in some countries. As bile acid
sequestrants are not systemically absorbed or altered by digestive enzymes, the
beneficial clinical effects are indirect. By binding the bile acids, the drugs
prevent the reabsorption of both the drug and cholesterol into the blood, and
thereby remove a large portion of the bile acids from the enterohepatic
circulation. The liver, depleted of bile, synthesizes more from hepatic
cholesterol, therefore increasing the hepatic demand for cholesterol and
increasing LDLR expression, which results in a decrease of circulating LDL.

8.3.2 EFFECTS ON LIPIDS

At the top daily dose of 24 g of cholestyramine, 20 g of colestipol, or 4.5 g of
colesevelam, a reduction in LDL-C of 18–25% has been observed. No major effect
on HDL-C has been reported, while TGs may increase in some predisposed
patients.274 Colesevelam can also reduce glucose levels in hyperglycaemic
patients.275

8.3.3 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY

In clinical trials, bile acid sequestrants have contributed greatly to the
demonstration of the efficacy of LDL-C lowering in reducing CV events in
hypercholesterolaemic people, with a benefit proportional to the degree of LDL-C
lowering. Of note, these studies were performed before many of the modern
treatment options were available.276–278

8.3.4 ADVERSE EFFECTS AND INTERACTIONS

Gastrointestinal (GI) adverse effects (most commonly flatulence, constipation,
dyspepsia, and nausea) are often present with these drugs, even at low doses,
which limits their practical use. These adverse effects can be attenuated by
beginning treatment at low doses and ingesting ample fluid with the drug. The
dose should be increased gradually. Reduced absorption of fat-soluble vitamins
has been reported. Furthermore, these drugs may increase circulating TG levels
in certain patients.

Bile acid sequestrants have major drug interactions with several commonly
prescribed drugs, and must therefore be administered either 4 h before or 1 h
after other drugs. Colesevelam is better tolerated and has fewer interactions
with other drugs, and can be taken together with statins and several other
drugs.279

8.4 PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 INHIBITORS

8.4.1 MECHANISM OF ACTION

Recently, a new class of drugs, PCSK9 inhibitors, has become available that
targets a protein (PCSK9) involved in the control of the LDLR.280 Elevated
concentration or function of this protein in plasma reduces LDLR expression by
promoting, upon binding, LDLR lysosomal catabolism and a subsequent increase in
plasma LDL concentrations, while lower concentration or function of PCSK9 is
related to lower plasma LDL-C levels.281 Therapeutic strategies have been
developed mainly using mAbs; the mechanism of action relates to the reduction of
the plasma level of PCSK9, which in turn is not available to bind the LDLR.
Since this interaction triggers the intracellular degradation of the LDLR, lower
levels of circulating PCSK9 will result in increased expression of LDLRs at the
cell surface and therefore in a reduction of circulating LDL-C levels.281
Currently, the only approved PCSK9 inhibitors are two fully human mAbs,
alirocumab and evolocumab. Statin treatment increases circulating PCSK9 serum
levels,282 and thus the best effect of these mAbs has been demonstrated in
combination with statins.

8.4.2 EFFECTS ON LIPIDS

8.4.2.1 LOW-DENSITY LIPOPROTEIN CHOLESTEROL.

In clinical trials, alirocumab and evolocumab—either alone or in combination
with statins, and/or other lipid-lowering therapies—have been shown to
significantly reduce LDL-C levels on average by 60%, depending on dose. The
efficacy appears to be largely independent of any background therapy. In
combination with high-intensity or maximally tolerated statins, alirocumab and
evolocumab reduced LDL-C by 46–73% more than placebo, and by 30% more than
ezetimibe. Among patients in whom statins cannot be prescribed, PCSK9 inhibition
reduced LDL-C when administered in combination with ezetimibe.283 Both
alirocumab and evolocumab have also been shown to effectively lower LDL-C levels
in patients who are at high CV risk, including those with DM.284

Given the mechanism of action, these drugs are effective at reducing LDL-C in
all patients capable of expressing LDLR in the liver. Therefore, this
pharmacological approach is effective in the vast majority of patients,
including those with HeFH and, albeit to a lower level, those with HoFH with
residual LDLR expression. Receptor-deficient HoFH responds poorly to the
therapy.285

8.4.2.2 TRIGLYCERIDES AND HIGH-DENSITY LIPOPROTEIN CHOLESTEROL.

These highly efficacious LDL-lowering agents also lower TG levels, and increase
those of HDL-C and ApoA-I as a function of the dosing regimen. In phase II
trials, evolocumab lowered TG levels by 26%, and raised HDL-C and ApoA-I by 9
and 4%, respectively; similar findings have been reported for alirocumab.286,287
However, the TG effect must be confirmed in populations with higher starting
plasma TG levels.

8.4.2.3 LIPOPROTEIN(A).

In contrast to statins, inhibiting PCSK9 with mAbs also reduces Lp(a) plasma
levels. Pooled results of phase II trials have shown that treatment leads to an
Lp(a) reduction of about 30–40%.288,289 While recent investigations have
attempted to unravel the mechanism, it remains unclear. However, it appears to
be distinct from that of statins, which also enhance LDLR function but do not
lower circulating Lp(a) levels in humans. The relative contribution of this
effect to the reduction of risk remains to be addressed in appropriately
designed studies.

8.4.3 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY

Early preliminary data from phase III trials suggests a reduction of CV events
in line with the LDL-C reduction achieved.286,290,291

Recently, two major studies were completed: the Further Cardiovascular Outcomes
Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and the
Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During
Treatment With Alirocumab (ODYSSEY Outcomes) trials.119,120 The designs of the
trials were similar with regard to the settings of secondary prevention and
background therapy; however, the populations enrolled had either stable CHD,
peripheral arterial disease (PAD), or stroke; or a recent (median 2.6 months)
ACS, respectively. The relative benefit ranged from 15–20% reductions in the
risk of the primary endpoints. Both studies had relatively short follow-up
periods and the evidence from statin trials indicates that the clinical benefits
of LDL-lowering may only emerge after about 1 year,51 so these trials may have
underestimated the potential impact of longer-term treatment.120,290

In the FOURIER trial,119 27 564 patients with atherosclerotic CVD, and LDL-C
levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy,
were randomly assigned to receive evolocumab or placebo. Allocation to
evolocumab reduced median LDL-C from 2.38 mmol/L (92 mg/dL) at baseline to a
mean of 0.78 mmol/L (30 mg/dL) at 48 weeks. After a median follow-up of 2.2
years, evolocumab treatment significantly reduced the risk of the primary
endpoint (composite of CV death, MI, stroke, hospitalization for unstable
angina, or coronary revascularization) by 15% [hazard ratio (HR) 0.85, 95% CI
0.79–0.92]. An analysis of the time to benefit also showed that there was a
lower benefit in the first year than in subsequent years, consistent with the
effects of statins observed within the CTT meta-analysis.268 In the FOURIER
trial, allocation to evolocumab did not reduce the risk of CV mortality (HR
1.05, 95% CI 0.88–1.25) or all-cause mortality.

The ODYSSEY Outcomes trial randomized 18 924 patients after hospitalization for
acute MI or unstable angina, treated with statins, and with LDL-C ≥1.8 mmol/L
(≥70 mg/dL), non-HDL cholesterol ≥2.6 mmol/L (≥100 mg/dL), or ApoB ≥80 mg/dL, to
receive injections of alirocumab or matching placebo. Allocation to alirocumab
reduced the mean baseline LDL-C from 2.38 mmol/L (92 mg/dL) to 1.24 mmol/L (48
mg/dL) at 12 months. There was a 15% relative reduction in the primary outcome
(composite of CHD death, non-fatal MI, ischaemic stroke, or unstable angina
requiring hospitalization) (HR 0.85, 95% CI 0.78–0.93) after a median follow-up
of 2.8 years.120 Although there was a significant reduction in all-cause
mortality in the ODYSSEY trial, this was an exploratory outcome and was not
supported by a significant effect on CV death.

8.4.4 ADVERSE EFFECTS AND INTERACTIONS

Anti-PCSK9 mAbs are injected subcutaneously, every other week or once a month,
at different doses depending on the agent used. The potential for interaction
with orally absorbed drugs is absent, as they will not interfere with
pharmacokinetics or pharmacodynamics. Among the most frequently reported side
effects are itching at the site of injection and flu-like symptoms.292 In some
studies, an increase of patient-reported neurocognitive effects has been
described.293 However, the EBBINGHAUS trial,231 which was specifically designed
to detect neurocognitive function changes, was reassuring, as were the safety
reports in both the FOURIER and ODYSSEY trials. Mendelian randomization studies
have also suggested that PCSK9 inhibition may increase the risk of DM with an
LDL-C-related effect, as apparently occurs for statins.294 To date, no signal
has emerged from RCTs.295–297 Although large long-term trials of PCSK9
inhibitors are needed to rule out these and other potential side effects of
inhibition of PCSK9,298 7 year data from the IMPROVE-IT study have shown that
prolonged low LDL-C concentrations are not associated with any clear adverse
effects.299

A potential problem of long-term antibody treatment is the occurrence of
autoantibodies. Evolocumab and alirocumab are fully human antibodies and,
therefore, theoretically less likely to induce autoantibodies. To date, only
very few cases of antidrug antibodies have been reported, and no reduction of
LDL-C lowering has been observed, but long-term use needs to be monitored.
Indeed, the development programme for a third PCSK9 inhibitor, bococizumab, a
humanized antibody, was discontinued because of an increase of neutralizing
antibodies, which resulted in the attenuation of the LDL-C-lowering effect over
time, as well as a higher rate of injection site reactions.300 However, although
PCSK9 inhibitors are very effective drugs that can reduce LDL-C and CV events on
top of statin and/or ezetimibe treatment, considering the costs of the
treatments and the limited data on long-term safety, these drugs are likely to
be considered cost-effective only in those patients at very high-risk of ASCVD,
and their use may not be possible in some countries with limited healthcare
resources.

8.5 LOMITAPIDE

The microsomal TG transfer protein (MTP) transfers TGs and phospholipids from
the endoplasmic reticulum to ApoB, as a necessary step in the formation of VLDL.
MTP inhibition thus prevents the formation of VLDL in the liver and of
chylomicrons in the intestine.

Lomitapide is an MTP inhibitor designed for o.d. oral treatment of HoFH. In an
open-label, single-arm titration study evaluating lomitapide as adjunct therapy
to statins, with or without apheresis and a low-fat diet,301 LDL-C was reduced
by 50% from baseline at 26 weeks and by 44% at 56 weeks. Lomitapide was also
shown to decrease the frequency of apheresis in HoFH patients. It should be
noted that the drug’s effect on CV outcomes has not yet been determined.

As a consequence of its mechanism of action, lomitapide has been shown to be
associated with increased aminotransferase levels, which most likely reflects
the increased fat in the liver, as well as poor GI tolerability.301,302 The GI
side effects were the most frequent reasons preventing a further increase in the
dose of lomitapide in clinical trials.301 However, it has been noted that the
frequency and intensity of GI side effects generally decrease with time.
Therefore, prescription of lomitapide requires careful patient education and
liver function monitoring during therapy.

8.6 MIPOMERSEN

Mipomersen is an antisense oligonucleotide able to bind the messenger RNA (mRNA)
of ApoB-100, which triggers the selective degradation of mRNA molecules. After
subcutaneous injection, the oligonucleotide is preferentially transported to the
liver, where it binds to a specific mRNA preventing the translation of ApoB
protein and, consequently, reducing the production of atherogenic lipids and
lipoproteins, including LDL and Lp(a).303 An adjunct to lipid-lowering
medications and diet, mipomersen is indicated to reduce LDL-C in patients with
HoFH. Mipomersen is currently approved by the US Food and Drug Administration
(FDA), but not by the European Medicines Agency (EMA).

Reactions at the injection site are the most common adverse effects observed in
patients treated with mipomersen.304 However, the main concerns regarding
mipomersen’s safety are related to liver toxicity. Mipomersen may lead to the
development of steatosis. Treated patients have shown a higher increase of liver
fat from baseline compared with patients randomized to placebo.303 The efficacy
and safety of long-term mipomersen treatment are currently under evaluation in
patients with severe HeFH, and in statin-‘intolerant’ patients.

8.7 FIBRATES

8.7.1 MECHANISM OF ACTION

Fibrates are agonists of peroxisome proliferator-activated receptor-α (PPAR-α),
acting via transcription factors regulating, among other things, various steps
in lipid and lipoprotein metabolism. As a consequence, fibrates have good
efficacy in lowering fasting TG levels, as well as post-prandial TGs and TG-rich
lipoprotein (TRL) remnant particles.

8.7.2 EFFECTS ON LIPIDS

Clinical impacts on lipid profiles vary among members of the fibrate class, but
are estimated to reach a 50% reduction of the TG level, a ≤20% reduction of the
LDL-C level (but a paradoxical small LDL-C increase may be observed with high TG
levels), and an increase of the HDL-C level of ≤20%. The magnitude of effect is
highly dependent on the baseline lipid levels.305 Both the HDL-raising and
TG-lowering effects of fibrates have been reported to be markedly less (∼5 and
∼20%, respectively) in long-term intervention trials in people with T2DM but
without elevated levels of TGs.306,307

8.7.3 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY

The clinical effects of fibrates have been primarily illustrated by six RCTs:
the Helsinki Heart Study (HHS), Veterans Affairs High Density Lipoprotein
Intervention Trial (VA-HIT), Bezafibrate Infarction Prevention (BIP), Lower
Extremity Arterial Disease Event Reduction (LEADER), Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD), and Action to Control Cardiovascular
Risk in Diabetes (ACCORD) trials; in the latter trial, fenofibrate was added to
statin therapy.306–311 In CV outcome trials of fibrates, the risk reduction
appeared to be proportional to the degree of non-HDL-C lowering.50

Although the HHS reported a significant reduction in CVD outcomes with
gemfibrozil, neither the FIELD nor the ACCORD studies involving fenofibrate
showed a reduction in total CVD outcomes. The LEADER trial included male
participants with lower-extremity arterial disease and failed to show that
bezafibrate could lead to a clinically important reduction in CVD combined
endpoints. Decreases in the rates of non-fatal MI were reported, although often
as a result of post hoc analyses. The effect was most evident in people with
elevated TG/low HDL-C levels. However, the data on other outcome parameters have
remained equivocal. Only one study, ACCORD, has analysed the effect of a fibrate
as an add-on treatment to a statin. No overall benefit was reported in two
recent meta-analyses.312,313 Results from other meta-analyses suggest reduced
major CVD events in patients with high TGs and low HDL-C in fibrate-treated
patients, but no decrease in CVD or total mortality.314–316 Thus, the overall
efficacy of fibrates on CVD outcomes is much less robust than that of statins.
Recently, a new selective PPAR-α modulator (pemafibrate) has been reported to
have marked efficacy in reducing TRLs.317 The study, Pemafibrate to Reduce
Cardiovascular OutcoMes by Reducing Triglycerides IN PatiENts With DiabeTes
(PROMINENT), is an ongoing CVD outcome trial designed to evaluate the efficacy
of pemafibrate in some 10 000 high-risk diabetic patients with high TG and low
HDL-C levels.318 Overall, the potential CV benefits of fibrates require further
confirmation.

8.7.4 ADVERSE EFFECTS AND INTERACTIONS

Fibrates are generally well tolerated with mild adverse effects, GI disturbances
being reported in <5% of patients, and skin rashes in 2%.319 In general,
myopathy, liver enzyme elevations, and cholelithiasis represent the most
well-known adverse effects associated with fibrate therapy.319 The risk of
myopathy has been reported to be 5.5-fold greater with fibrate monotherapy
(mainly with gemfibrozil) compared with a statin, and it varies with different
fibrates and statins used in combination. This is explained by the
pharmacological interactions between the metabolism of different fibrates and
pathways of glucuronidation of statins. Gemfibrozil inhibits the metabolism of
statins via the glucuronidation pathway, which leads to marked increases in
plasma concentrations of statins.320 As fenofibrate does not share the same
pharmacokinetic pathways as gemfibrozil, the risk of myopathy is much less with
this combination therapy.319

As a class, fibrates have been reported to raise both serum creatinine and
homocysteine levels in both short- and long-term studies. The increase of serum
creatinine by fibrate therapy seems to be fully reversible when the drug is
stopped. Data from meta-analyses suggest that a reduction of calculated
glomerular filtration rate (GFR) does not reflect any adverse effects on kidney
function.315 Fibrates are associated with a slightly increased risk of
pancreatitis.321 The increase in homocysteine levels caused by fibrates has been
considered to be relatively neutral with respect to CVD risk. However, a
fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and
ApoA1 levels, and this effect may contribute to the smaller than estimated
benefits of fenofibrate in CV outcome parameters.322

8.8 N-3 FATTY ACIDS

8.8.1 MECHANISM OF ACTION

The n-3 (or omega-3) fatty acids [eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA)] can be used at pharmacological doses to lower TGs.
n-3 fatty acids (2–4 g/day) affect serum lipids and lipoproteins, in particular
VLDL concentrations. The underlying mechanism is poorly understood, although it
may be related, at least in part, to their ability to interact with PPARs and to
decreased secretion of ApoB.

8.8.2 EFFECTS ON LIPIDS

n-3 fatty acids reduce TGs, but their effects on other lipoproteins are trivial.
More detailed data on clinical outcomes are needed to justify wide use of
prescription n-3 fatty acids.323 The recommended doses of total EPA and DHA to
lower TGs have varied between 2–4 g/day. Three recent studies in people with
high TGs using EPA reported a significant reduction in serum TG levels of up to
45% in a dose-dependent manner.324–326 The efficacy of omega-3 fatty acids in
lowering serum TGs has also been reported in meta-analyses.157 Recently, the
EpanoVa fOr Lowering Very high triglyceridEs II (EVOLVE II) trial confirmed the
efficacy of omega-3 fatty acids in lowering serum TGs.327

8.8.3 EFFECT ON CARDIOVASCULAR MORBIDITY AND MORTALITY

A Cochrane meta-analysis, including 112 059 people from 79 trials, reported no
overall effect of omega-3 PUFAs on total mortality (relative risk 0.98, 95% CI
0.90–1.03) or CV events (relative risk 0.99, 95% Cl 0.94–1.04), with only a
suggestion that omega-3 fatty acids reduced CHD events (relative risk 0.93, 95%
Cl 0.88–0.97).328 Recently, the A Study of Cardiovascular Events iN Diabetes
(ASCEND) trial,329 which randomly assigned 15 480 patients with DM but without
atherosclerotic CV disease to n-3 fatty acids or placebo, showed no significant
difference in the risk of serious vascular events after a mean follow-up of 7.4
years (relative risk 1.00, 95% Cl 0.91–1.09).

The data remain inconclusive and the clinical efficacy of omega-3 fatty acids
appears to be related to non-lipid effects.330,331 Moreover, studies with
omega-3 fatty acids have suffered from the dose used (1 g/day), which does not
affect plasma lipids to a large extent, as the dose required to decrease plasma
TGs is >2 g/day. The Reduction of Cardiovascular Events with EPA-Intervention
Trial (REDUCE-IT)195 aimed to evaluate the potential benefits of omega-3 oil
(EPA) on ASCVD outcomes in people with elevated serum TGs; the trial enrolled
∼8000 patients on statin therapy, with LDL-C levels between 1.0–2.6 mmol/L
(41–100 mg/dL) and various CV risk factors, including persistent elevated TGs
between 1.7–5.6 mmol/L (150–499 mg/dL), and either established ASCVD or DM, and
at least one other CV risk factor. Use of high doses (2 g b.i.d.) of EPA as
compared with placebo (mineral oil) resulted in a ∼25% relative risk reduction
(P < 0.001) in major adverse CV events (MACE). Another randomized
placebo-controlled trial, Outcomes Study to Assess STatin Residual Risk
Reduction with EpaNova in HiGh CV Risk PatienTs with Hypertriglyceridemia
(STRENGTH),332 which aims to determine whether reduction of TRLs and remnants in
statin-treated patients will provide additional ASCVD risk reduction, is
ongoing. The VITamin D and OmegA-3 TriaL (VITAL), which reported recently, was a
2×2 factorial design study in which healthy participants were randomized in a
1:1 fashion to either vitamin D3 (at a dose of 2000 IU per day) vs. matching
placebo, and n-3 fatty acids (1 g per day as a fish-oil capsule containing 840
mg of n-3 fatty acids, including 460 mg of EPA and 380 mg of DHA) vs. matching
placebo. It showed that supplementation with either n-3 fatty acids at a dose of
1 g/day, or vitamin D3 at a dose of 2000 IU/day, was not effective for primary
prevention of CV or cancer events among healthy middle-aged men and women over 5
years of follow-up.333

8.8.4 SAFETY AND INTERACTIONS

The administration of n-3 fatty acids appears to be safe and devoid of
clinically significant interactions. The most common side effect is GI
disturbance. The antithrombotic effects may increase the propensity for
bleeding, especially when given in addition to aspirin/clopidogrel. Recently,
data from one study have associated a risk of prostate cancer with high dietary
intake of n-3 PUFAs.334

8.9 NICOTINIC ACID

Nicotinic acid has key action sites in both the liver and adipose tissue. In the
liver, nicotinic acid inhibits diacylglycerol acyltransferase-2 resulting in
decreased secretion of VLDL particles, which is also reflected in reductions of
plasma levels of both IDL and LDL particles.335 Nicotinic acid primarily raises
HDL-C and ApoA1 by stimulating ApoA1 production in the liver.335 Two large
randomized trials with nicotinic acid—one with extended-release niacin66 and one
with niacin plus laropiprant67—have shown no beneficial effect and an increased
frequency of serious adverse effects. No medication containing nicotinic acid is
currently approved in Europe.

8.10 CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS

To date, the pharmacological approach that has led to the greatest elevations in
HDL-C levels has been direct inhibition of CETP by small-molecule inhibitors,
which may induce an increase in HDL-C by ≥100% on a dose-dependent basis.
Torcetrapib was studied in the Investigation of Lipid Level Management to
Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was
stopped early due to increased mortality.336 Dalcetrapib raises HDL-C levels by
30–40% with no appreciable effect on LDL-C, offering specific insight into pure
HDL-C raising. However, dalcetrapib failed to show any benefit in ACS patients
in the dal-OUTCOMES trial. Evacetrapib, which raises HDL-C levels by 130% and
lowers LDL-C by 37%, was studied in the ACCELERATE trial,63 which was terminated
due to futility. Recently, anacetrapib, which raises HDL-C and ApoA-I levels (by
104 and 36%, respectively), and lowers LDL-C and ApoB (by 17 and 18%,
respectively), was studied in the REVEAL trial. Anacetrapib reduced major
coronary events by 9% over a median of 4.1 years.64 The magnitude of the
relative risk reduction appeared to be consistent with the magnitude of LDL-C-
or non-HDL-C-level lowering.337 This drug has not been submitted for regulatory
approval.

8.11 FUTURE PERSPECTIVES

8.11.1 NEW APPROACHES TO REDUCE LOW-DENSITY LIPOPROTEIN CHOLESTEROL

An alternative approach targeting PCSK9 consists of RNA interference. In a phase
I and a phase II trial, the small interfering RNA (siRNA) molecule
inclisiran—which inhibits the synthesis of PCSK9—reduced LDL-C by up to 50% and
the reduction was dose-dependent. Reductions in PCSK9 and LDL-C levels were
maintained for ≤6 months.338,339 No specific serious adverse events were
observed. HPS4/TIMI65/ORION4, with a planned mean duration of 5 years, is
currently comparing inclisiran vs. placebo among 15 000 patients with a prior MI
or stroke.

Bempedoic acid is a novel, first-in-class, oral small molecule that inhibits
cholesterol synthesis by inhibiting the action of ATP citrate lyase, a cytosolic
enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.340 So far,
it has been tested in diabetic patients, and patients with or without statin
‘intolerance’. In monotherapy, bempedoic acid reduces LDL-C levels by ∼30% and
by about 50% in combination with ezetimibe. Bempedoic acid is currently being
tested in phase III trials and some trials have been completed.341,342

8.11.2 NEW APPROACHES TO REDUCE TRIGLYCERIDE-RICH LIPOPROTEINS AND THEIR
REMNANTS

As genetic studies indicate that angiopoietin-like protein 3 (ANGPTL3)
deficiency protects against atherosclerotic disease and that this relationship
is causal,343 an ANGPTL3 antibody (evinacumab) is being developed. Evinacumab
has been shown to decrease TGs, LDL-C, and Lp(a) levels in HoFH patients.344
Another approach that is currently being investigated is the inhibition of
ANGPTL3 production by antisense oligonucleotides.345 IONIS-ANGPTL3-LRx, an
antisense oligonucleotide targeting ANGPTL3, another critical protein in the
clearance of TRLs, reduces plasma TGs by about 85%. Thus, the future may yield
tools to improve TRL clearance that will be reflected in the atherogenic load of
the remnant particles.

The rapid development of gene-silencing technology has allowed proteins
(ApoC-III) that are critical in the regulation of TRL clearance processes to be
targeted. A second-generation antisense oligonucleotide targeting ApoC-III mRNA
has been developed.346 Two phase III trials have evaluated the safety and
efficacy of volanesorsen in patients with elevated TG levels.347,348
Volanesorsen reduced plasma TGs by ∼70% and ApoC-III by 80–90%.349 The EMA
recently issued a marketing authorization for Waylivra (volanesorsen) as an
adjunct to diet in adult patients with genetically confirmed familial
chylomicronaemia syndrome (FCS) who are at high-risk for pancreatitis, in whom
response to diet and TG-lowering therapy has been inadequate.

8.11.3 NEW APPROACHES TO INCREASE HIGH-DENSITY LIPOPROTEIN CHOLESTEROL

Although genetic studies suggest that low HDL-C levels are not a cause of ASCVD,
casting doubt on the possibilities of future treatment options to raising HDL-C
levels with attenuation of CVD, major developments in the search for efficacious
agents to raise HDL-C and ApoA1 levels with concomitant benefits on
atherosclerosis and CV events are on the horizon. On the one hand, interest is
focused on ApoA1 mimetic peptides and recombinant forms of HDL possessing
potential for in vivo HDL particle remodelling and enhanced cardioprotective
activity.350 On the other, agents that enhance catabolism of TG-rich
lipoproteins, such as the antisense oligonucleotide to ApoC-III, and which lead
to a concomitant reduction in TGs (∼70%) and a marked elevation in HDL-C (∼40%)
in hypertriglyceridemia, are under development.351 Importantly, however, we
currently lack understanding of the relationship between the modality of raising
HDL/ApoA-I levels and a possible antiatherogenic function of HDL particles.

8.11.4 NEW APPROACHES TO REDUCE LIPOPROTEIN(A) LEVELS

Another approach under study is the selective decrease of Lp(a) concentrations.
RNA-based therapies are now being evaluated in clinical settings. Results from
studies of an antisense oligonucleotide in patients with normal Lp(a) values as
well as in patients with elevated Lp(a) concentrations have shown a reduction of
>90%.352 These approaches are currently being evaluated in phase II–III studies
and an outcome trial is planned to study whether Lp(a) reduction translates into
risk reduction.

8.12 STRATEGIES TO CONTROL PLASMA CHOLESTEROL

Recommendations for pharmacological low-density lipoprotein cholesterol lowering

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 =
proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

For definitions see Table 7.

Open in new tab

Recommendations for pharmacological low-density lipoprotein cholesterol lowering

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 =
proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

For definitions see Table 7.

Open in new tab

Although LDL-C goals are attained with monotherapy in many patients, a
significant proportion of patients at high-risk or with very high LDL-C levels
need additional treatment. In this case, combination therapy is reasonable. In
patients at very-high risk and with persistent high-risk despite being treated
with a maximally tolerated statin, combination with ezetimibe is recommended
and, if still not at goal, the addition of a PCSK9 inhibitor is recommended (see
Figure 4 and Recommendations for pharmacological low-density lipoprotein
cholesterol lowering). Of note, addition of a PCSK9 inhibitor directly to a
statin is also feasible120,290 (Figure 4).

Figure 3
Open in new tabDownload slide

Expected clinical benefits of low-density lipoprotein cholesterol-lowering
therapies. The expected clinical benefits of treatment to lower low-density
lipoprotein cholesterol for any person can be estimated; it depends on the
intensity of therapy, the baseline low-density lipoprotein cholesterol level,
the expected absolute achieved reduction in low-density lipoprotein cholesterol,
and the baseline estimated risk of atherosclerotic cardiovascular disease. The
intensity of therapy should be selected to achieve the recommended proportional
reduction in low-density lipoprotein cholesterol based on the person’s estimated
risk of atherosclerotic cardiovascular disease. Multiplying the proportional
reduction in low-density lipoprotein cholesterol by a person’s baseline
low-density lipoprotein cholesterol level estimates the expected absolute
reduction in low-density lipoprotein cholesterol that is likely to be achieved
with that therapy. Because each 1.0 mmol/L absolute reduction in low-density
lipoprotein cholesterol is associated with a 20% reduction in the risk of
cardiovascular events, larger absolute reductions in low-density lipoprotein
cholesterol lead to larger proportional reductions in risk. Multiplying the
proportional reduction in risk expected for the achieved absolute reduction in
low-density lipoprotein cholesterol by a person’s estimated baseline risk of
atherosclerotic cardiovascular disease determines the expected absolute risk
reduction for that person. LDL-C = low-density lipoprotein cholesterol; PCSK9 =
proprotein convertase subtilisin/kexin type 9.

Figure 4
Open in new tabDownload slide

(A) Treatment algorithm for pharmacological low-density lipoprotein cholesterol
lowering. (B) Treatment goals for low-density lipoprotein cholesterol across
categories of total cardiovascular disease risk. ASCVD = atherosclerotic
cardiovascular disease; BP = blood pressure; CKD = chronic kidney disease; CV =
cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration
rate; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein
cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; SCORE =
Systematic Coronary Risk Estimation; T1DM = type 1 DM; T2DM = type 2 DM; TC =
total cholesterol.

As shown in Figure 3, the expected clinical benefit of treatment to lower the
LDL-C level of any person can be estimated; it depends on the intensity of
therapy, the baseline LDL-C level, and the baseline estimated risk of ASCVD.
This simple algorithm can be used to help clinicians select the appropriate
therapy and quantify the expected benefits of LDL-C-lowering therapy to help
inform discussions with patients. For ease of reference, Supplementary Table 3
provides a summary of the absolute LDL-C reductions that can be achieved with
various therapeutic approaches at particular baseline levels of LDL-C.

8.13 STRATEGIES TO CONTROL PLASMA TRIGLYCERIDES

Although CVD risk is increased when fasting TGs are >1.7 mmol/L (>150 mg/dL),56
the use of drugs to lower TG levels may only be considered in high-risk patients
when TGs are >2.3 mmol/L (>200 mg/dL) and TGs cannot be lowered by lifestyle
measures. The available pharmacological interventions include statins, fibrates,
PCSK9 inhibitors, and n-3 PUFAs. A meta-analysis of 10 trials included people
treated with various agents that reduce serum TGs (fibrates, niacin, and n-3
PUFAs) and reported a 12% reduction in CV outcomes.354 Recently, the REDUCE-IT
trial194 demonstrated that in statin-treated patients with high CV risk with
fasting TG levels between 135–499 mg/dL (1.52–1.63 mmol/L), high-dose icosapent
ethyl, a highly purified and stable EPA (2 g) taken b.i.d., significantly
reduced the risk of ischaemic events, including CV death, by about one-quarter
over a median follow-up of 4.9 years. In addition, the VITAL trial showed that
n-3 fatty acids at the lower dose of 1 g/day were not effective for primary
prevention of CV or cancer events among healthy middle-aged men and women over 5
years of follow-up.333 Recommendations for the treatment of HTG are shown below.

Recommendations for drug treatment of patients with hypertriglyceridaemia

CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; PUFA
= polyunsaturated fatty acids; TG = triglyceride.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for drug treatment of patients with hypertriglyceridaemia

CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; PUFA
= polyunsaturated fatty acids; TG = triglyceride.

Class of recommendation.

Level of evidence.

Open in new tab

9 MANAGEMENT OF DYSLIPIDAEMIAS IN DIFFERENT CLINICAL SETTINGS

9.1 FAMILIAL DYSLIPIDAEMIAS

Plasma lipid levels are, to a very large extent, determined by genetic factors.
In its more extreme forms this is manifested as familial dyslipidaemias. A
number of monogenic lipid disorders have been identified; among these, FH is the
most common and is strongly related to CVD (Table 11). In general, in a patient
with dyslipidaemia, the pattern of inheritance commonly does not suggest that
there is a major single gene (monogenic) disorder causing the abnormality;
rather, it stems from the inheritance of more than one gene variant affecting
lipoprotein metabolism that, on its own, might have relatively little effect,
but in combination with another or others has a greater influence on TC, TGs, or
HDL-C. The pattern of inheritance is polygenic.357 It is common to find that
high LDL-C, high TG, or low HDL-C levels affect several family members.

Table 11

Genetic disorders of lipoprotein metabolism

Disorder . Prevalence . Gene(s) . Effect on lipoproteins . HeFH 1 in 200–250

* LDLR

* APO B

* PCSK9

↑LDL-C HoFH 1 in 160 000–320 000

* LDLR

* APO B

* PCSK9

↑↑LDL-C FCH 1 in 100/200 USF1 + modifying genes ↑LDL-C ↑VLDL-C ↑ApoB Familial
dysbetalipoproteinaemia 1 in 5000 APO E ↑↑IDL and chylomicron remnants
(βVLDL) Familial lipoprotein lipase deficiency (familial chylomicron syndrome) 2
in 106

* LPL

* APO C2

* ApoAV, GPIHBP1

* LMF1

↑↑chylomicrons and VLDL-C Tangier disease (analphalipoproteinaemia) 1 in
106 ABCA1 ↓↓HDL-C Familial LCAT deficiency 1 in 106 LCAT ↓HDL-C

Disorder . Prevalence . Gene(s) . Effect on lipoproteins . HeFH 1 in 200–250

* LDLR

* APO B

* PCSK9

↑LDL-C HoFH 1 in 160 000–320 000

* LDLR

* APO B

* PCSK9

* LPL

* APO C2

* ApoAV, GPIHBP1

* LMF1

↑↑chylomicrons and VLDL-C Tangier disease (analphalipoproteinaemia) 1 in
106 ABCA1 ↓↓HDL-C Familial LCAT deficiency 1 in 106 LCAT ↓HDL-C

Apo = apolipoprotein; FCH = familial combined hyperlipidaemia; HDL-C =
high-density lipoprotein cholesterol; HeFH = heterozygous familial
hypercholesterolaemia; HoFH = homozygous familial hypercholesterolaemia; IDL =
intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase;
LDL-C = low-density lipoprotein cholesterol; VLDL = very low-density lipoprotein
cholesterol.

Open in new tab
Table 11

Genetic disorders of lipoprotein metabolism

Disorder . Prevalence . Gene(s) . Effect on lipoproteins . HeFH 1 in 200–250

* LDLR

* APO B

* PCSK9

↑LDL-C HoFH 1 in 160 000–320 000

* LDLR

* APO B

* PCSK9

* LPL

* APO C2

* ApoAV, GPIHBP1

* LMF1

↑↑chylomicrons and VLDL-C Tangier disease (analphalipoproteinaemia) 1 in
106 ABCA1 ↓↓HDL-C Familial LCAT deficiency 1 in 106 LCAT ↓HDL-C

Disorder . Prevalence . Gene(s) . Effect on lipoproteins . HeFH 1 in 200–250

* LDLR

* APO B

* PCSK9

↑LDL-C HoFH 1 in 160 000–320 000

* LDLR

* APO B

* PCSK9

* LPL

* APO C2

* ApoAV, GPIHBP1

* LMF1

↑↑chylomicrons and VLDL-C Tangier disease (analphalipoproteinaemia) 1 in
106 ABCA1 ↓↓HDL-C Familial LCAT deficiency 1 in 106 LCAT ↓HDL-C

Open in new tab

9.1.1 FAMILIAL COMBINED HYPERLIPIDAEMIA

Familial combined hyperlipidaemia (FCH) is a highly prevalent mixed
dyslipidaemia (1:100–200) characterized by elevated levels of LDL-C, TGs, or
both, and is an important cause of premature CAD. FCH is a complex disease, and
the phenotype is determined by the interaction of multiple susceptibility genes
and the environment. It has considerable overlap with the dyslipidaemic
phenotypes of T2DM and MetS. Even within a family, the phenotype shows high
inter- and intrapersonal variability based on lipid values (TGs, LDL-C, HDL-C,
and ApoB). FCH has no monogenic component and is not linked to a single genetic
cause, but the phenotype is high LDL-C and/or high TGs.358,359 Therefore, the
diagnosis is commonly missed in clinical practice; the combination of ApoB >120
mg/dL and TGs >1.5 mmol/L (>133 mg/dL) with a family history of premature CVD
can be used to identify people who most probably have FCH.360

The concept of mixed dyslipidaemia is also valuable clinically in assessing CV
risk. It emphasizes both the importance of considering family history in
deciding how rigorously to treat dyslipidaemia and that elevated LDL-C levels
portend a higher risk when HTG is also present. Statin treatment decreases CV
risk by the same relative amount in people with HTG as in those without. Because
the absolute risk is often greater in those with HTG, they may therefore benefit
greatly from LDL-lowering therapy.

9.1.2 FAMILIAL HYPERCHOLESTEROLAEMIA

9.1.2.1 HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA.

FH is a common codominant monogenic dyslipidaemia causing premature CVD due to
lifelong elevation of plasma levels of LDL-C. If left untreated, men and women
with HeFH typically develop early CAD before the ages of 55 and 60 years
respectively. The risk of CHD among individuals with definite or probable HeFH
is estimated to be increased at least 10-fold. However, early diagnosis and
appropriate treatment can dramatically reduce the risk for CAD.

The prevalence of HeFH in the population is estimated to be 1/200–250,361
translating to a total number of cases between 14–34 million worldwide.362,363
Only a minor fraction of these cases is identified and properly treated.

FH is a monogenic disease caused by loss-of-function mutations in the LDLR or
apoB genes, or a gain-of-function mutation in the PCSK9 gene; around 95% of FH
cases are caused by mutations in LDLR. More than 1000 different mutations that
cause FH have been identified in LDLR. The different mutations cause reduced
function or complete loss-of-function, the latter being associated with more
severe hypercholesterolaemia and CVD.

The diagnosis of FH is usually based on clinical presentation. The commonly used
criteria from the Dutch Lipid Clinic Network are shown in Table 12. Other
criteria are the Simon Broome register or the WHO criteria.364,365

Table 12

Dutch Lipid Clinic Network diagnostic criteria for familial
hypercholesterolaemia

Criteria . Points . 1) Family history First-degree relative with known premature
(men aged <55 years; women <60 years) coronary or vascular disease, or
first-degree relative with known LDL-C above the 95th percentile 1 First-degree
relative with tendinous xanthomata and/or arcus cornealis, or children aged <18
years with LDL-C above the 95th percentile 2 2) Clinical history Patient with
premature (men aged <55 years; women <60 years) CAD 2 Patient with premature
(men aged <55 years; women <60 years) cerebral or peripheral vascular
disease 1 3) Physical examinationa Tendinous xanthomata 6 Arcus cornealis before
age 45 years 4 4) LDL-C levels (without treatment) LDL-C ≥8.5 mmol/L (≥325
mg/dL) 8 LDL-C 6.5–8.4 mmol/L (251–325 mg/dL) 5 LDL-C 5.0–6.4 mmol/L (191–250
mg/dL) 3 LDL-C 4.0–4.9 mmol/L (155–190 mg/dL) 1 5) DNA analysis Functional
mutation in the LDLR, apoB, or PCSK9 genes 8 Choose only one score per group,
the highest applicable; diagnosis is based on the total number of points
obtained A ‘definite’ FH diagnosis requires >8 points A ‘probable’ FH diagnosis
requires 6–8 points A ‘possible’ FH diagnosis requires 3–5 points

CAD = coronary artery disease; FH = familial hypercholesterolaemia; LDL-C =
low-density lipoprotein cholesterol; PCSK9 = proprotein convertase
subtilisin/kexin type 9.

Exclusive of each other (i.e. maximum 6 points if both are present).

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Table 12

Dutch Lipid Clinic Network diagnostic criteria for familial
hypercholesterolaemia

CAD = coronary artery disease; FH = familial hypercholesterolaemia; LDL-C =
low-density lipoprotein cholesterol; PCSK9 = proprotein convertase
subtilisin/kexin type 9.

Exclusive of each other (i.e. maximum 6 points if both are present).

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The diagnosis can be verified by showing causative mutations in the pathogenic
genes. However, in most studies, the frequency of detectable mutations in
patients with a clinically definite or probable HeFH is between 60–80%. This
suggests that a considerable proportion of patients with FH have either a
polygenic cause of the disease or that other genes, yet to be identified, are
involved.

Genetic testing and cascade screening. Probands (index cases) should be
identified according to the following criteria:

* TC ≥8 mmol/L (≥310 mg/dL) without treatment in an adult or adult family
member (or >95th percentile by age and gender for country);

* Premature CHD in the patient or a family member;

* Tendon xanthomas in the patient or a family member; or

* Sudden premature cardiac death in a family member.

Cascade screening of family members of a known index case allows for the
efficient identification of new cases. Cascade screening is best performed by a
lipid clinic. In most families, the cases may be identified with TC or LDL-C
analysis; however, genetic testing is recommended when the causative mutation is
known.

Cholesterol-lowering treatment should be initiated as soon as possible after a
diagnosis has been made. To improve risk assessment, the use of imaging
techniques to detect asymptomatic atherosclerosis is recommended. The concept of
cumulative cholesterol burden illustrates the importance of early treatment (for
children, see below). Treatment should be initiated with high-intensity statin
therapy, in most cases in combination with ezetimibe. In FH patients at
very-high risk of ASCVD due to a prior history of ASCVD or another major risk
factor, LDL-C goals are a ≥50% reduction of LDL-C from baseline and an LDL-C
<1.4 mmol/L (<55 mg/dL). In the absence of ASCVD or another major risk factor,
patients with FH are categorized as high-risk, and LDL-C goals are a ≥50%
reduction of LDL-C from baseline and an LDL-C <1.8 mmol/L (<70 mg/dL).

PCSK9 inhibitors lower LDL-C levels by up to 60% on top of statins. Two RCTs
have reported a beneficial effect on clinical endpoints in ASCVD patients
without FH.119,120 PCSK9 inhibitors are recommended in very-high-risk patients
with FH if the treatment goal is not achieved on maximal tolerated statin plus
ezetimibe. PCSK9 inhibitors are also recommended in FH patients who cannot
tolerate statins.366,367

Recommendations for the detection and treatment of patients with HeFH are shown
below.

Recommendations for the detection and treatment of patients with heterozygous
familial hypercholesterolaemia

ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease;
CVD = cardiovascular disease; FH = familial hypercholesterolaemia; HoFH =
homozygous FH; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein
convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

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Recommendations for the detection and treatment of patients with heterozygous
familial hypercholesterolaemia

Class of recommendation.

Level of evidence.

Open in new tab

9.1.2.2 HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA.

HoFH is a rare and life-threatening disease. The clinical picture is
characterized by extensive xanthomas, marked premature and progressive CVD, and
TC >13 mmol/L (>500 mg/dL). Most patients develop CAD and aortic stenosis before
the age of 20 years and die before 30 years of age. The frequency of HoFH is
estimated to be 1/160 000–1/320 000. The early identification of these children
and prompt referral to a specialized clinic is crucial. The patients should be
treated with intensive LDL-lowering drug therapy and, when available, with
lipoprotein apheresis. This treatment (every 1–2 weeks) can decrease plasma
LDL-C levels by 55–70%. The procedure frequency may be adjusted for each patient
as lipid levels, symptoms, and other disease-related parameters change.
Maximally tolerated pharmacological therapy must be maintained.368 For a more
detailed discussion on HoFH, see the EAS consensus statements.366,368

9.1.2.3 FAMILIAL HYPERCHOLESTEROLAEMIA IN CHILDREN.

FH is diagnosed in children based on phenotypic criteria including elevated
LDL-C plus a family history of elevated LDL-C, premature CAD, and/or positive
genetic testing.369 Testing during childhood is optimal to discriminate between
FH and non-FH using LDL-C. In children with a family history of high cholesterol
or premature CHD, an accepted cut-off is ≥4.0 mmol/L (≥160 mg/dL). If a parent
has a known genetic defect, the diagnostic level for the child is ≥3.5 mmol/L
(≥130 mg/dL). If possible, genetic testing of the child is suggested.

Although there have been no placebo-controlled trials in children, observational
studies have suggested that early treatment can reduce LDL-C burden, improve
endothelial function, substantially attenuate the development of
atherosclerosis, and improve coronary outcomes.369–371 Treatment of children
with FH includes a healthy lifestyle and statin treatment. A heart-healthy diet
should be adopted early in life and statin treatment should be considered at
6–10 years of age. Statin treatment should be started with low doses and the
dose should be increased to reach goals.372 The goal in children >10 years of
age is an LDL-C <3.5 mmol/L (<135 mg/dL) and at younger ages a ≥50% reduction of
LDL-C.

9.1.3 FAMILIAL DYSBETALIPOPROTEINAEMIA

Familial dysbetalipoproteinaemia (i.e. type III hyperlipoproteinaemia; remnant
removal disease) is rare and is generally inherited as an autosomal recessive
disorder with variable penetrance. Familial dysbetalipoproteinaemia produces a
characteristic clinical syndrome in which both TC and TGs are elevated before
treatment, usually both in the range of 7–10 mmol/L. In severe cases, patients
develop tuberoeruptive xanthomas, particularly over the elbows and knees, and
palmar xanthomata in the skin creases of the hands and wrists. The risk of CAD
is very high, and accelerated atherosclerosis of the femoral and tibial arteries
is also prevalent. The syndrome is usually not expressed at a young age or in
women before menopause. The majority of cases are homozygous for the E2 isoform
of ApoE. ApoE is important for the hepatic clearance of chylomicron remnants and
IDL. ApoE2 binds less readily than the E3 and E4 isoforms to hepatic receptors.
However, without some coincidental cause of dyslipidaemia such as dyslipidaemia
associated with HTG, DM, obesity, or hypothyroidism,373–375 ApoE2 homozygosity
does not generally cause familial dysbetalipoproteinaemia.

The detection of ApoE2 homozygosity in a dyslipidaemic patient is diagnostic and
analysis of ApoE isoforms is now available in most clinical laboratories. The
presence of cholesterol remnants characteristic of familial
dysbetalipoproteinaemia can be reliably predicted on the basis of plasma levels
of cholesterol, TGs, and ApoB.376 If suspicion is confirmed, ApoE genotyping can
be performed. In older patients with xanthomata resembling those of familial
dysbetalipoproteinaemia who prove not to be homozygous for ApoE2, a paraprotein
should be sought. The treatment of familial dysbetalipoproteinaemia should be
undertaken in a specialist clinic. Most cases respond well to treatment with a
statin or, if dominated by high TGs, a ﬁbrate; often a combination of a statin
and a ﬁbrate may be needed.

9.1.4 GENETIC CAUSES OF HYPERTRIGLYCERIDAEMIA

Although the genetic aetiology for HTG seems to be very complex, recent data
have extended our genetic understanding of HTG, in particular that of
chylomicronaemia.37,226,377 Moderate elevation of TG levels (between 2.0–10.0
mmol/L) is caused by the polygenic effect of multiple genes influencing both
VLDL production and removal. Monogenic severe HTG causes chylomicronaemia,
pancreatitis, and lipid deposits. Thus far, mutations in six genes (LPL, apoC2,
apoA5, LMF1, GPIHBP1, and GPD1) with monogenic effects have been recognized to
lead to severe elevation of serum TGs due to disruption of the chylomicron
removal pathways. These mutations are inherited as autosomal recessive traits
and are rare. The profound defect in the catabolism of chylomicrons and VLDL
results in chylomicronaemia and TG levels >11.2 mmol/L (>1000 mg/dL), with
turbid and milky serum. Severe HTG is seen in patients who are homozygous or
compound heterozygous for mutations of the enzyme LPL, and in other genes linked
to the catabolism of TG-rich lipoproteins. Heterozygous carriers of these same
gene mutations commonly express moderate elevations of serum TG levels that
expose them to increased CVD risk.378 Recently, gene therapy for LPL deficiency
has been developed and tested in clinical trials,379 and the alipogene
tiparvovec was approved by the EMA in 2013. However, this therapy is no longer
available. A gain-of-function mutation in apoC3 that leads to high ApoC-III
levels can also cause severe HTG by inhibiting the activity of LPL, whereas
loss-of-function mutations are associated with a favourable lipid profile with
low TG levels.380 These findings have raised the possibility of ApoC-III being a
novel lipid drug target.

9.1.4.1 ACTION TO PREVENT ACUTE PANCREATITIS IN SEVERE HYPERTRIGLYCERIDAEMIA.

The risk of pancreatitis is clinically significant if TGs are >10 mmol/L (880
mg/dL), particularly when occurring in association with familial
chylomicronaemia, and actions to prevent acute pancreatitis are
mandatory.381,382 Notably, HTG is the cause of ∼10% of all cases with
pancreatitis, and patients can develop pancreatitis even when their TG
concentration is 5–10 mmol/L (440–880 mg/dL). Recent data from a prospective
cohort study reported that the risk of acute pancreatitis increased
significantly over the quartiles of serum TGs, highlighting the fact that, as a
risk factor, serum TGs may have been underestimated.383 Any factor that
increases VLDL production can aggravate the risk of pancreatitis, with alcohol
consumption being the most common contributing factor. Either a patient should
be admitted to hospital if symptomatic, or careful and close follow-up of the
patient’s TG values should be undertaken. Restriction of calories and fat
content (10–15% recommended) in the diet, and alcohol abstinence are obligatory.
Fibrate therapy (fenofibrate) should be initiated, with n-3 fatty acids (2–4
g/day) as adjunct therapy. Lomitapide may also be considered in severe cases.37
In patients with DM, insulin therapy should be initiated to achieve good
glycaemic control. In general, a sharp decrease of TG values is seen within 2–5
days. In the acute setting, plasmapheresis is able to rapidly lower TG
levels.384 Volanesorsen has been recently approved by the EMA as an adjunct to
diet in adult patients with genetically confirmed FCS who are at high-risk for
pancreatitis.

9.1.5 OTHER GENETIC DISORDERS OF LIPOPROTEIN METABOLISM

Sometimes patients are encountered with extremely low levels of LDL-C or HDL-C.
The most common form of genetic hypolipidaemia is hypobetalipoproteinaemia,
which is dominantly inherited and often due to truncation of ApoB. Serum LDL-C
is typically between 0.5–1.5 mmol/L (20–60 mg/dL). A more profound deficiency of
ApoB occurs in abetalipoproteinaemia when steatorrhoea, and neurological or
other complications require specialist treatment. Almost absent levels of HDL-C
occur in Tangier disease (analphalipoproteinaemia) and very low levels of HDL-C
occur in lecithin cholesterol acyltransferase (LCAT) deficiency. Both these
conditions are associated with distinct clinical syndromes and require
specialist investigation. Very high levels of HDL-C are detected in patients
with CETP deficiency. In the heterozygous form, levels of 2.0–2.3 mmol/L (80–90
mg/dL) are typically observed, and levels ≥5 mmol/L (≥200 mg/dL) are observed in
homozygotes. This is not associated with atherosclerotic disease and may be
associated with reduced risk.

Lysosomal acid lipase deficiency or cholesterol ester storage disease (in
children with Wolman disease) is a rare cause (recessive transmission) of
elevated LDL-C and low HDL-C, accompanied by hepatomegaly and microvesicular
hepatosteatosis. Statin treatment does decrease LDL-C levels and could therefore
prevent ASCVD in these patients, but it cannot stop the progression of liver
damage. Treatment with a PCSK9 inhibitor may lead to an even greater overload of
lysosomes.385 Enzyme replacement therapy with sebelipase alfa might offer a
treatment solution in the near future.386

9.2 WOMEN

Few randomized trials of statin therapy have reported independently significant
CV benefits in women,387,389 chiefly because women have not been adequately
represented in statin trials.

9.2.1 EFFECTS OF STATINS IN PRIMARY AND SECONDARY PREVENTION

There has previously been controversy over whether statins are effective for
primary prevention in women. Using published data, a 2013 Cochrane analysis
showed that statin therapy reduced all-cause mortality, vascular events, and
revascularizations in primary prevention, and the proportional effects in women
were similar to those in men.213 The CTT collaboration has provided a more
complete assessment of the evidence through a comprehensive analysis of IPD from
22 trials of statins vs. control and five trials of more- vs. less-intensive
statin therapy.35 Overall, 46 675 (27%) of 174 149 participants were women, and
after adjustment for non-gender differences, the proportional reductions per
mmol/L reduction in LDL-C in major vascular events, major coronary events,
coronary revascularization, and stroke were similar in women and men.35

9.2.2 NON-STATIN LIPID-LOWERING DRUGS

Definitive evidence of the cardioprotective effects of non-statin drugs that
lower LDL-C is now available, and the beneficial effects are similar in both
women and men. In the IMPROVE-IT study,33 the relative benefit of adding
ezetimibe to simvastatin was similar in women and men.33 In the ACCORD lipid
study, there was no evidence that fenofibrate added to the effects of
simvastatin in patients with T2DM,306 but an analysis of the FIELD study showed
consistent CV event reduction in both women and men.389 Several outcome trials
assessing the effects of adding a PCSK9 inhibitor to high-intensity statin
therapy have now been reported, with similar proportional reductions in major
vascular events in women and men.120,286,290

9.2.3 HORMONE THERAPY

Currently prescribed third-generation, low-dose oestrogen–progestin oral
contraceptives do not appear to increase adverse coronary events390 and can be
used, after baseline lipid profile assessment, in women with acceptable TC
levels. In contrast, alternative contraceptive measures should be recommended in
women with hypercholesterolaemia [LDL-C >4 mmol/L (>160 mg/dL)] or with multiple
risk factors, and in those at high-risk of thrombotic events.391 Oestrogen
replacement therapy, despite some favourable effects on lipid profiles, has not
been demonstrated to reduce CV risk and cannot be recommended for CVD prevention
in women.392 No lipid-lowering drugs should be administered during pregnancy and
the period of breastfeeding because data on possible adverse effects are
lacking. However, bile acid sequestrants may be considered.

Box 6 lists the main measures in the management of dyslipidaemia in women.

Box 6

Management of dyslipidaemia in women

Statin treatment is recommended for primary prevention of ASCVD in high-risk
women.34,35 Statins are recommended for secondary prevention in women with the
same indications and goals as in men.34,35 Lipid-lowering drugs should not be
given when pregnancy is planned, during pregnancy, or during the breastfeeding
period. However, for severe FH patients, bile acid sequestrants (which are not
absorbed) and/or LDL apheresis may be considered.

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL = low-density lipoprotein.

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Box 6

Management of dyslipidaemia in women

ASCVD = atherosclerotic cardiovascular disease; FH = familial
hypercholesterolaemia; LDL = low-density lipoprotein.

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9.3 OLDER PEOPLE

The proportion of older people (defined herein as those aged >65 years) in
society is increasing and, as a consequence, >80% of individuals who die from
CVD are >65 years of age. The proportion of patients with MI >85 years of age
has increased several-fold.393

A meta-analysis of observational studies has shown that higher TC is associated
with increased CAD mortality at all ages.62,394 However, since the absolute risk
of CAD is higher in older persons, the associated absolute increase in risk for
a given increment in TC is larger with increasing age.217

9.3.1 EFFECTS OF STATINS IN PRIMARY AND SECONDARY PREVENTION

The use of statin therapy declines with increasing age, reflecting differences
in both prescription and compliance.395,396 This trend is even more prominent
among older patients who do not have evidence of occlusive vascular disease.396
One explanation for this pattern may be uncertainty about the effects of statins
in older people due to the relatively small number of people aged >75 years who
have been included in statin trials.233,397,398 The CTT collaboration recently
provided a comprehensive assessment of the randomized evidence on the effects of
statin therapy at different ages.217 Among 186 854 participants in 28 trials, 14
483 (8%) were aged >75 years at randomization. Overall, statin therapy produced
a 21% relative reduction in major vascular events (relative risk 0.79, 95% CI
0.77–0.81) per 1.0 mmol/L reduction in LDL-C, and there was direct evidence of
benefit among those aged >75 years. The relative reduction in major vascular
events was similar, irrespective of age, among patients with pre-existing
vascular disease, but appeared smaller among older individuals not known to have
vascular disease. Therefore, the available evidence from trials indicates that
statin therapy produces significant reductions in major vascular events
irrespective of age. However, there is less direct evidence of benefit among
patients aged >75 years who do not already have evidence of occlusive vascular
disease, and this limitation is currently being addressed by the STAtin therapy
for Reducing Events in the Elderly (STAREE) trial in Australia.

9.3.2 ADVERSE EFFECTS, INTERACTIONS, AND ADHERENCE

The safety and adverse effects of statins are a matter of special concern in
older adults because they often have comorbidities, take multiple medications,
and have altered pharmacokinetics and pharmacodynamics. Statin–drug interactions
are a concern, primarily because of their potential to increase muscle-related
statin-associated adverse effects such as myalgia without CK elevation, myopathy
with CK elevation, and the rare but serious rhabdomyolysis. It is recommended
that a statin is started at a low dose if there is significant renal impairment
and/or the potential for drug interactions, and then titrated upwards to achieve
LDL-C treatment goals.

The recommendations for the treatment of dyslipidaemias in older people are
shown below.

Recommendations for the treatment of dyslipidaemias in older people (aged >65
years)

ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein
cholesterol.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for the treatment of dyslipidaemias in older people (aged >65
years)

ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein
cholesterol.

Class of recommendation.

Level of evidence.

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9.4 DIABETES AND METABOLIC SYNDROME

The number of people with DM will increase from ∼415 million today up to 550
million by 2030, but the situation may get even worse.399 Despite significant
advantages in the management strategies that lessen atherosclerotic CVD risk
factors, CVD has remained the leading cause of morbidity and mortality in
patients with T2DM. The good news is that fatal CVD outcomes have declined
significantly in both T1DM and T2DM between 1998 and 2014.400 DM itself is an
independent risk factor for CVD and is associated with a higher risk of CVD,
even more so in women. The difference in CVD risk between individuals with and
without DM has narrowed substantially over the last few decades,401 and there
are strong associations between DM and vascular outcomes.402,403 Recent data
indicate that DM per se increases CVD risk about two-fold on average, but the
risk is subject to wide variation depending on the population and current
aggressive prophylactic therapy.401,404 Importantly, those with DM and CAD are
at substantially higher CVD risk for future events. In T2DM, the risk of ASCVD
is strongly determined by the presence of target organ damage—including
nephropathy (microalbuminuria), neuropathy, or retinopathy—with the risks
increasing in relation to the number of conditions present.405 Hypertension,
dyslipidaemia, abdominal obesity, and non-alcoholic fatty liver disease (NAFLD)
commonly coexist with T2DM and further aggravate the risk, which is highest in
people with T2DM and multiple cardiometabolic risk factors.406–408 Importantly,
DM confers excess mortality risk following ACS despite modern therapies,
highlighting the poor prognosis of coronary patients with T2DM and the need for
intensive therapy.409

How to capture the extra risk beyond the traditional risk factors in clinical
practice is a debated issue. A practical approach is that if one component is
identified, a systematic search should be made for the others.410

9.4.1 SPECIFIC FEATURES OF DYSLIPIDAEMIA IN INSULIN RESISTANCE AND TYPE 2
DIABETES MELLITUS

Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein
abnormalities that are metabolically interrelated. The increase in large VLDL
particles in T2DM initiates a sequence of events that generates atherogenic
remnants, small dense LDL, and small TG-rich dense HDL particles.411 These
components are not isolated abnormalities but are closely linked to each other.
Both LDL and HDL particles show variable compositional changes that are
reflected in their functions. Notably, ApoC-III levels are increased in people
with T2DM.412 High ApoC-III concentrations prevent the clearance of both TRLs
and remnants, resulting in prolonged residence times of these particles in the
circulation.413,414 In fact, the defective catabolism of TRLs seems to be a more
important contributor to the elevation of plasma TGs than the increased
production rate leading to an excess of remnant particles. Together, TRL
remnants, small dense LDL, and small dense HDL comprise the atherogenic lipid
profile, which is also characterized by an increase in ApoB concentration due to
an increased number of ApoB-containing particles. Importantly, TRLs—including
chylomicrons, VLDL, and their remnants—carry a single ApoB molecule, also like
LDL particles. Therefore, the malignant nature of diabetic dyslipidaemia is not
always revealed by the lipid measures used in clinical practice, as LDL-C levels
may remain within the normal range. It may be better revealed by non-HDL-C
levels.415 Elevation of TGs or low HDL-C levels in the fasting or post-prandial
state is seen in about one-half of all people with T2DM,416,417 and is also
often present in people with abdominal adiposity, insulin resistance or impaired
glucose tolerance.413

Box 7 summarizes dyslipidaemia in MetS and T2DM.

Box 7

Summary of dyslipidaemia in metabolic syndrome and type 2 diabetes mellitus

Dyslipidaemia represents a cluster of lipid and lipoprotein abnormalities,
including elevation of both fasting and post-prandial TG, ApoB, and small dense
LDL, and low HDL-C and ApoA1 levels. Non-HDL-C or ApoB are good markers of TRLs
and remnants, and are a secondary objective of therapy. Non-HDL-C <2.6 mmol/L
(<100 mg/dL) and ApoB <80 mg/dL are desirable in those at high-risk, and
non-HDL-C <2.2 mmol/L (<85 mg/dL) and ApoB <65 mg/dL in those at very high-risk.
For those at very high-risk with recurrent ASCVD events, a goal of non-HDL-C
<1.8 mmol/L (<70 mg/dL) and ApoB <55 mg/dL may be considered. Atherogenic
dyslipidaemia is one of the major risk factors for CVD in people with type 2
diabetes, and in people with abdominal obesity and insulin resistance or
impaired glucose tolerance.

Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CVD =
cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C =
low-density lipoprotein cholesterol; TG = triglyceride; TRLs = triglyceride-rich
lipoproteins.

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Box 7

Summary of dyslipidaemia in metabolic syndrome and type 2 diabetes mellitus

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9.4.2 EVIDENCE FOR LIPID-LOWERING THERAPY

9.4.2.1 LOW-DENSITY LIPOPROTEIN CHOLESTEROL.

LDL-C is the primary target of lipid-lowering therapy in patients with DM.
Trials specifically performed in people with T2DM, as well as subsets of
individuals with DM in major statin trials, have consistently demonstrated
significant benefits of statin therapy on CVD events in people with T2DM.418
Statin therapy reduces the 5 year incidence of major CVD events by 23% per 1
mmol/L reduction in LDL-C, regardless of the initial LDL-C level or other
baseline characteristics based on meta-analysis.418 The CTT meta-analysis
further indicates that people with T2DM will have a relative risk reduction that
is comparable to that seen in non-diabetic patients; however, being at higher
absolute risk, the absolute benefit will be greater, resulting in a lower number
needed to treat (NNT). Thus, statin therapy is the first-line treatment for
LDL-C lowering and for the reduction of CVD burden.419

Ezetimibe lowers LDL-C by ∼24% and, when added to statin therapy, decreases the
risk of major vascular events.33 The relative risk reduction in major vascular
events is proportional to the absolute degree of LDL-C lowering and consistent
with the relationship seen for statins. The subset of patients with DM in
IMPROVE-IT had, as expected, a higher rate of major vascular events than
patients without DM (46 vs. 31% 7 year Kaplan–Meier rate in the placebo arm).
Ezetimibe appeared particularly efficacious in patients with DM, with a relative
risk reduction of 15% (95% CI 6–22%) and an absolute risk reduction of 5.5%.299

The mAb PCSK9 inhibitors evolocumab and alirocumab lower LDL-C levels by ∼60%
and, when added to statin therapy, decrease the risk of major vascular
events.119 In the FOURIER study, the relative risk reduction for major vascular
events was similar in patients with and without DM; however, given the higher
baseline risk in patients with DM, the absolute risk reductions tended to be
greater in patients with DM (2.7% absolute decrease in major vascular events
over 3 years).297 Of note, the achieved LDL-C in the evolocumab arm was 0.8
mmol/L. The same benefits were also recently demonstrated for diabetic patients
after ACS in the ODYSSEY trial.420

Recent studies have suggested an increased incidence of DM in patients treated
with statins.247 These observations have been seen in Mendelian randomization
studies and in clinical trials, although the effect appears greatest in patients
already at high risk for DM (e.g. those with pre-diabetes). These observations
should not lessen our attention to the treatment of patients, as the overall
benefits in CV event reduction remain and greatly outweigh the increased
incidence of DM. In RCTs, neither ezetimibe nor the PCSK9 inhibitors have been
reported to increase the risk of DM.297

9.4.2.2 TRIGLYCERIDES AND HIGH-DENSITY LIPOPROTEIN CHOLESTEROL.

Lifestyle modification provides the first option to improve atherogenic
dyslipidaemia due to its multifaceted effects. Weight loss is, in most cases,
the most effective measure since it is associated with very pronounced effects
on plasma TG and HDL levels, together with a modest decrease in TC and LDL-C
levels. Moderate-to-heavy aerobic exercise is also associated with improvement
of the plasma lipid profile by reducing TG levels and increasing HDL-C
concentrations. In relation to diet composition, besides the need to eliminate
trans fat, the available evidence supports the reduction of saturated fat intake
and its substitution with unsaturated fat, as well as the replacement of a major
proportion of refined starchy foods and simple sugars with fibre-rich foods like
fruits, vegetables, and wholegrains.179

The clinical benefits achieved by the treatment of high TG and low HDL-C levels
(frequently seen with DM) are still a matter of debate, as the effects of
fenofibrate therapy on the major outcome (MACE) remained negative in both the
FIELD and the ACCORD studies performed in T2DM cohorts.306,307 In a post hoc
analysis of the FIELD study, fenofibrate reduced CVD events by 27% in those with
elevated TGs [∼2.3 mmol/L (200 mg/dL)] and increased HDL-C levels (NNT = 23).416
The ACCORD trial confirmed the following: patients who had both TG levels in the
higher third [∼2.3 mmol/L (200 mg/dL)] and an HDL-C level in the lower third
[≤0.4 mmol/L (≤34 mg/dL)], representing 17% of all participants, appeared to
benefit from the addition of fenofibrate to simvastatin.306

Recently, post-trial follow-up of the ACCORD lipid trial participants reported
the beneficial effect of fenofibrate in people with HTG and low HDL-C levels at
baseline.421 Consistent with these findings, a meta-analysis of fibrates in the
prevention of CVD in 11 590 people with T2DM showed that fibrates significantly
reduced the risk of non-fatal MI by 21%, but had no effect on the risk of
overall mortality or coronary mortality.422 In CV outcome trials of fibrates,
the risk reduction has appeared to simply be proportional to the degree of
non-HDL-C lowering.50

Overall, available data indicate that diabetic patients with atherogenic
dyslipidaemia may derive clinical benefits from TG-lowering therapy as an add-on
to statin treatment.354 The ongoing PROMINENT trial is exploring the efficacy of
pemafibrate, a new selective PPAR-α modulator, in reducing CVD outcomes in ∼10
000 diabetic patients with atherogenic dyslipidaemia on a statin.317,423

There are limited data on the impacts on CVD of adding omega-3 fatty acids to
statin therapy in patients with high plasma TG levels who are treated with
statins. The REDUCE-IT trial examined the effects of icosapent ethyl 2 g b.i.d.
on CV events in 8179 high-risk patients with HTG who were taking a statin. Over
a median of 4.9 years, there was a significant (P < 0.001) 25% reduction in the
composite primary outcome of CV death, non-fatal MI, non-fatal stroke, coronary
revascularization, or unstable angina, corresponding with an absolute reduction
of 4.8%, which was offset by a 1% increased absolute risk of hospitalization for
atrial fibrillation or flutter.194 The STRENGTH trial is investigating the
effect of omega-3 fatty acids, in addition to a statin, in individuals with HTG
and low HDL-C levels who are at high-risk for CVD. The ASCEND trial was a
randomized 2×2 factorial design study of aspirin and omega-3 fatty acid
supplements for the primary prevention of CV events in people with DM, but not
specifically with HTG. Among 15 480 people randomized to omega-3 fatty acid
supplements vs. placebo over a mean follow-up of 7.4 years, there was no
significant effect (HR 0.97, 95% CI 0.87–1.08) on serious vascular events
[non-fatal MI, non-fatal stroke, transient ischaemic attack (TIA), or vascular
death].329,424–426

9.4.3 TYPE 1 DIABETES MELLITUS

T1DM is associated with high CVD risk, in particular in patients with
microalbuminuria and renal disease.427 Conclusive evidence supports the
proposition that hyperglycaemia accelerates atherosclerosis. Emerging evidence
highlights the frequent coexistence of MetS with T1DM, resulting in the
so-called double diabetes increasing CVD risk.428

The lipid profile in T1DM patients with good glycaemic control is ‘supernormal’,
and is characterized by subnormal TG and LDL-C levels, whereas HDL-C levels are
usually within the upper normal range or slightly elevated. This is explained by
subcutaneous administration of insulin that increases LPL activity in adipose
tissue and skeletal muscle, and consequently the turnover rate of VLDL
particles.429 However, there are potentially atherogenic changes in the
compositions of both HDL and LDL particles.

Consistent data have demonstrated the efficacy of statins in preventing CV
events and reducing CV mortality in patients with DM, with no evidence of sex
differences.430,431 A meta-analysis including 18 686 patients with DM
demonstrated that a statin-induced reduction of LDL-C yielded a 9% reduction in
all-cause mortality and a 21% reduction in the incidence of major CV events per
1.0 mmol/L (40mg/dL) lower LDL cholesterol.418 Similar benefits were seen in
patients with T1DM and T2DM. In diabetic patients with ACS, intensive statin
treatment led to a reduction in all-cause mortality and CV death, and
contributed to a reduction in atheroma progression.432

9.4.4 MANAGEMENT OF DYSLIPIDAEMIA FOR PREGNANT WOMEN WITH DIABETES

In both T1DM and young-onset T2DM patients, there is a paucity of evidence to
indicate the age at which statin therapy should be initiated. To guide an
approach, statins are not indicated in pregnancy,433 and should be avoided in
both T1DM and T2DM individuals who are planning pregnancy. If diabetic
individuals aged ≤30 years have no evidence of vascular damage and, in
particular, microalbuminuria, it seems reasonable to delay statin therapy in
asymptomatic patients until the age of 30. Below this age, statin therapy should
be managed on a case-by-case basis, taking into account the presence of
microalbuminuria, end organ damage, and ambient LDL-C levels.

Recommendations for the treatment of dyslipidaemias in DM are shown in the table
below.

Recommendations for the treatment of dyslipidaemias in diabetes mellitus

LDL-C = low-density lipoprotein cholesterol; T1DM = type 1 diabetes mellitus;
T2DM = type 2 diabetes mellitus.

Class of recommendation.

Level of evidence.

See Table 6.

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Recommendations for the treatment of dyslipidaemias in diabetes mellitus

LDL-C = low-density lipoprotein cholesterol; T1DM = type 1 diabetes mellitus;
T2DM = type 2 diabetes mellitus.

Class of recommendation.

Level of evidence.

See Table 6.

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9.5 PATIENTS WITH ACUTE CORONARY SYNDROMES AND PATIENTS UNDERGOING PERCUTANEOUS
CORONARY INTERVENTION

Patients who present with ACS are at increased risk of experiencing recurrent CV
events. For these patients, lipid management should be undertaken in the context
of a comprehensive global risk reduction strategy including lifestyle
adaptations, risk factor management, and the implementation of cardioprotective
drug strategies. Ideally, patients should be signed up to cardiac rehabilitation
programmes to enhance the control of lipid levels434 and improve overall
survival following ACS.435 Despite the acknowledged clinical benefits of
lowering LDL-C in patients with ACS,436 attainment of LDL-C target values
remains suboptimal in this very high-risk setting.437

9.5.1 LIPID-LOWERING THERAPY IN PATIENTS WITH ACUTE CORONARY SYNDROMES

LDL-C levels tend to decrease during the first days of ACS and therefore a lipid
profile should be obtained as soon as possible after admission for ACS. Patients
do not have to be fasting as this has little impact on LDL-C levels.100
Lipid-lowering treatment should be initiated as early as possible to increase
patient adherence after discharge. Lipid levels should be re-evaluated 4–6 weeks
after ACS to determine whether treatment goals have been achieved and to check
for any safety issues; the therapeutic regimen can then be adapted accordingly.

9.5.1.1 STATINS.

Data from RCTs and meta-analyses indicate that routine early use of
high-intensity statin therapy is associated with rapid and sustained clinical
benefits.438–442 We recommend the initiation of high-intensity statin therapy in
all statin-naïve ACS patients with no contraindication, regardless of initial
LDL-C values; the treatment goal is to reach a 50% LDL-C reduction from baseline
and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). In those with recurrent events
within 2 years while taking maximally tolerated statin therapy, a goal of <1.0
mmol/L (<40 mg/dL) for LDL-C should be considered. The intensity of statin
therapy should be increased in those patients receiving low- or
moderate-intensity statin treatment at presentation, unless there is a definite
history of intolerance to high-intensity statin therapy. The use of
lower-intensity statin therapy should be considered in patients at increased
risk of adverse effects with high-intensity statin therapy, such as in the
elderly, patients diagnosed with hepatic or renal impairment, or in the case of
a potential risk of drug–drug interactions with other essential concomitant
therapies.

Regarding the timing of statin treatment initiation, the Statins Evaluation in
Coronary Procedures and Revascularization (SECURE-PCI) randomized,
placebo-controlled trial recently assessed the impact of peri-procedural loading
with atorvastatin [two loading doses of 80 mg, before and 24 h after the planned
percutaneous coronary intervention (PCI)] on MACE at 30 days in 4191 patients
with ACS and planned invasive management.443 All patients received atorvastatin
40 mg per day starting 24 h after the second loading dose. The authors found no
significant treatment benefit in the overall study population. In a
pre-specified analysis, a significant 28% relative risk reduction in MACE was
observed among patients who underwent PCI (65% of all patients). The benefit was
even more pronounced (46% relative risk reduction) in a post hoc analysis
including 865 ST-elevation MI (STEMI) patients undergoing reperfusion by primary
PCI.443 Based on current evidence, we recommend the initiation of high-intensity
statin therapy during the first 1–4 days of hospitalization for the index
ACS.438–442 Moreover, pre-treatment (or loading dose for patients already on a
statin) with a high-intensity statin should be considered in ACS patients with
planned invasive management.443

9.5.1.2 EZETIMIBE.

In the IMPROVE-IT trial, the addition of ezetimibe to simvastatin therapy
provided an additional benefit (6.4% relative risk reduction in the composite
clinical endpoint) to post-ACS patients.33 The clinical benefit of adding
ezetimibe was consistent across patient subgroups299,444 and also led to a
reduction of total CV events,445 stroke,446 and rehospitalizations.447 Patients
at higher atherothrombotic risk [as assessed by the TIMI (Thrombolysis In
Myocardial Infarction) risk score for secondary prevention] benefitted the most
from the addition of ezetimibe.448 In another randomized, open-label trial
including 1734 patients with ACS, the addition of ezetimibe to
moderate-intensity statin (pitavastatin 2 mg) therapy failed to improve outcomes
overall, but did reduce the composite primary endpoint (death, MI, stroke,
unstable angina, and ischaemia-driven revascularization) during 3.9-year
follow-up in patients with increased intestinal absorption of cholesterol (as
assessed by elevated levels of sitosterol)449; however, this finding requires
further confirmation.

9.5.1.3 PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 INHIBITORS.

In the FOURIER trial, which included 27 564 patients with atherosclerotic CV
disease, the addition of evolocumab to statin therapy (69% high-intensity
therapy) resulted in a 15% relative risk reduction of the composite primary
endpoint throughout a 2.2 year follow-up. Results were consistent in the
subgroup of patients with a history of MI (81% of all patients).119,450 A
subanalysis of the FOURIER trial showed that patients who achieved the lowest
LDL-C values under PCSK9 treatment also had the lowest risk of future MACE.451
In the ODYSSEY Outcomes trial, which included 18 924 patients with recent ACS
(1–12 months prior to enrolment, median 2.6 months), alirocumab added to statin
therapy (89% high-intensity therapy) also resulted in a 15% relative risk
reduction in the primary composite endpoint and was associated with a 15%
relative reduction in all-cause mortality throughout a 2.8 year follow-up.120 No
serious side effects or safety concerns were reported in these two large trials.
The optimal timing of initiating PCSK9 inhibition after ACS and its impact on
clinical outcomes remain to be determined. Regarding the timing of PCSK9
inhibitor treatment initiation, post hoc analyses from the FOURIER trial have
shown that the closer to the event this is done, the better. Treatment
initiation with PCSK9 inhibitors during the acute phase of ACS is under
investigation in the EVOlocumab for Early Reduction of LDL-cholesterol Levels in
Patients With Acute Coronary Syndromes (EVOPACS) trial.452 Based on current
evidence, we recommend the initiation of treatment with PCSK9 inhibitors in
patients with ACS who do not reach their respective LDL-C goals (as outlined in
Table 7) after 4–6 weeks of maximum tolerated statin and ezetimibe therapy. In
patients who present with an ACS and whose LDL-C levels are not at goal, despite
already taking a maximally tolerated statin dose and ezetimibe prior to the
event, the addition of a PCSK9 inhibitor early after the event (during the
hospitalization for the ACS event if possible) should be considered.

9.5.1.4 N-3 POLYUNSATURATED FATTY ACIDS.

Oral supplementation with highly purified n-3 PUFAs reduced mortality in
survivors of MI in one study [Gruppo Italiano per lo Studio della Sopravvivenza
nell'Infarto Miocardico-Prevenzione (GISSI-P)] but failed to affect clinical
outcomes in subsequent trials using contemporary secondary prevention therapies.
A recent meta-analysis of available RCTs showed no reduction in mortality, MI,
or major vascular events associated with n-3 PUFAs, including the subgroup of
patients with known CAD.453 Therefore, routine treatment with n-3 PUFAs cannot
be recommended.

9.5.1.5 CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS.

In 2007, a large prospective study using the CETP inhibitor torcetrapib failed
to show any clinical benefit in more than 15 000 high-risk patients, and was
potentially harmful.336 The CETP inhibitors dalcetrapib (in >30 000 patients
with recent ACS65) and evacetrapib (in >12 000 high-risk patients63) were
investigated in 2012 and 2017, respectively. Neither clinical study was able to
show any clinical benefit associated with CETP inhibitors.65 More recently, the
REVEAL study investigated anacetrapib in >30 000 patients with atherosclerotic
vascular disease and resulted in a lower incidence of MACE compared with placebo
after 4 years, with no safety concerns.64 However, this compound was not filed
for marketing authorization.

9.5.2 LIPID-LOWERING THERAPY IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY
INTERVENTION

In a meta-analysis of 13 randomized studies including 3341 patients who were
planned to undergo PCI, pre-treatment with a high-dose statin (statin-naïve
patients, 11 studies) or a high-dose statin loading dose reduced the risk of
MACE (death, MI, or target vessel revascularization) by 44% both for
peri-procedural MI and MACE at 30 days.454 In all but one study, PCI was
performed in the setting of stable angina or in a non-emergency setting in
non-ST elevation ACS (NSTE-ACS). One of the studies that was included in the
meta-analysis showed an improvement in coronary flow when primary PCI was used
for the treatment of STEMI.455 A routine strategy of either short pre-treatment
or loading (on the background of pre-existing therapy) with a high-dose statin
before PCI should be considered in elective PCI or NSTE-ACS.454,456,457

In addition, pre-treatment with a statin has also been shown to reduce the risk
of contrast-induced acute kidney injury after coronary angiography or
intervention.458

Recommendations for lipid-lowering therapy in patients with ACS and patients
undergoing PCI are summarized below.

Recommendations for lipid-lowering therapy in very-high-risk patients with acute
coronary syndromes

ACS = acute coronary syndrome; LDL-C = low-density lipoprotein cholesterol;
PCSK9 = proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for lipid-lowering therapy in very-high-risk patients with acute
coronary syndromes

ACS = acute coronary syndrome; LDL-C = low-density lipoprotein cholesterol;
PCSK9 = proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

Open in new tab

9.6 STROKE

Stroke has a heterogeneous aetiology, including cardiac thromboembolism [often
associated with atrial fibrillation, but also of uncertain source (embolic
stroke of undetermined source)], carotid artery and proximal aortic
atherosclerosis and thromboembolism, small-vessel CVD, and intracranial
haemorrhage (including intracerebral and subarachnoid haemorrhage).
Dyslipidaemia may play a variable role in the pathogenesis of stroke according
to the particular aetiology. The relationship between dyslipidaemia and
atherothrombotic events, including ischaemic stroke and TIA, is well recognized,
while the association of dyslipidaemia with other types of stroke is uncertain.
Notwithstanding, concomitant control of other aetiological factors, such as
hypertension, is of paramount importance.

Following ischaemic stroke or TIA, patients are at risk not only of recurrent
cerebrovascular events, but also of other major CV events, including MI.
Secondary prevention therapy with statins reduces the risk of recurrent stroke
(by 12% per mmol/L reduction in LDL cholesterol), MI, and vascular death.459,460
Statin pre-treatment at TIA onset was associated with reduced recurrent early
stroke risk in patients with carotid stenosis in a pooled data analysis,
supporting as-early-as-possible initiation of statins after stroke.460–462
Statin therapy may yield a small increase in the risk of haemorrhagic stroke,
but the evidence regarding this risk is uncertain.34,36,251,252

Recommendations for lipid-lowering therapy in very-high-risk patients undergoing
percutaneous coronary intervention

ACS = acute coronary syndrome; PCI = percutaneous coronary intervention.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for lipid-lowering therapy in very-high-risk patients undergoing
percutaneous coronary intervention

ACS = acute coronary syndrome; PCI = percutaneous coronary intervention.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for lipid-lowering therapy for the prevention of atherosclerotic
cardiovascular disease events in patients with prior ischaemic stroke

ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein
cholesterol; TIA = transient ischaemic attack.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for lipid-lowering therapy for the prevention of atherosclerotic
cardiovascular disease events in patients with prior ischaemic stroke

ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein
cholesterol; TIA = transient ischaemic attack.

Class of recommendation.

Level of evidence.

Open in new tab

9.7 HEART FAILURE AND VALVULAR DISEASES

9.7.1 PREVENTION OF INCIDENT HEART FAILURE IN CORONARY ARTERY DISEASE PATIENTS

Cholesterol lowering with statins reduces the incidence of HF in patients with
CAD (stable CAD or a history of ACS) without previous HF; this has been shown
consistently in RCTs that have compared statin vs. no statin treatment463,464 as
well as more-intensive vs. less-intensive statin therapy.465–468 A large-scale
meta-analysis of primary and secondary prevention RCTs with statins showed a
modest (10%) reduction in first non-fatal HF hospitalizations with statin
treatment, with no effect on HF death within the limited RCT period.469 There is
no evidence that statins can prevent HF of non-ischaemic origin.

9.7.2 CHRONIC HEART FAILURE

Two large RCTs466,470 (mainly including patients with systolic HF), as well as a
meta-analysis of 24 RCTs, have shown no benefit of statin treatment on CV
mortality or stroke;471 a reduction in HF hospitalizations,218,471 as well as a
small reduction in MI, was observed in a pooled analysis of the Controlled
Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-HF
trials.472 Based on current evidence, routine administration of statins in
patients with HF without other indications for their use (e.g. CAD) is not
recommended. Because there is no evidence of harm in patients on statin
treatment after the occurrence of HF, there is no need for statin
discontinuation for patients already on treatment.

There is no evidence regarding the effect of PCSK9 inhibition in patients with
chronic HF. In the recent PCSK9 clinical outcomes trials, FOURIER119 and ODYSSEY
Outcomes,120 PCSK9 inhibition in patients with atherosclerotic CVD or after an
ACS did not reduce the risk of HF hospitalization. In the BIOlogy Study to
TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study of 2174 patients
with worsening HF, multivariable analysis revealed a positive linear association
between PCSK9 levels and the risk of mortality, and the composite of mortality
and unplanned HF hospitalization.473 Similarly, there was a negative association
between LDLR levels and mortality, indicating a potential relationship between
the PCSK9–LDLR axis and outcomes among patients with HF that requires further
investigation.473,474

Treatment with n-3 PUFAs 1 g o.d. may confer a small benefit in patients with
chronic HF, as shown by a significant 9% relative risk reduction for mortality
in the GISSI-HF RCT.475

9.7.3 VALVULAR HEART DISEASES

Aortic stenosis increases the risk of CV events and mortality, and frequently
coexists with atherosclerotic CVD. Life-long high levels of LDL-C476 and
Lp(a)477 have been associated with incident aortic valve stenosis and aortic
valve calcification in genetic Mendelian randomization studies. Observational
studies have suggested possible beneficial effects of intensive lipid lowering
in slowing the progression of native valve aortic stenosis.478 However, this has
not been confirmed in RCTs,266,479–481 or in meta-analyses of observational and
randomized trials.482,483 Three modestly sized trials479–481 and one large
randomized trial (SEAS, which included 1873 patients treated with simvastatin 40
mg plus ezetimibe 10 mg or placebo)266 failed to show a reduction in the
clinical progression of aortic stenosis in patients with mild-to-moderate native
valve aortic stenosis. In a post hoc analysis of the SEAS trial, the efficacy of
lipid-lowering therapy in impeding the progression of aortic stenosis increased
with higher pre-treatment LDL-C levels and lower peak aortic jet velocity (i.e.
milder stenosis at baseline).484 Similarly, a post hoc analysis of three RCTs,
including patients without known aortic valve stenosis at baseline [Treating to
New Targets (TNT), Incremental Decrease In End-points Through Aggressive
Lipid-lowering (IDEAL), and Stroke Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL)] showed no impact of high-dose vs. usual-dose statin
therapy on the incidence of aortic valve stenosis.485 In patients who underwent
transcatheter aortic valve replacement, statin therapy was associated with
improved outcomes in a small observational study.486

Aortic valve sclerosis (calcification of the aortic leaflets without significant
transvalvular pressure gradient) is associated with an increased risk of CAD
even in the absence of increased risk profiles. Whether or not statins may be
useful both for aortic valve disease and CAD progression in such patients
warrants further investigation.487

Recommendations for lipid-lowering therapy in patients with HF and valvular
diseases are shown below.

Recommendations for the treatment of dyslipidaemias in chronic heart failure or
valvular heart diseases

CAD = coronary artery disease; HF = heart failure.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for the treatment of dyslipidaemias in chronic heart failure or
valvular heart diseases

CAD = coronary artery disease; HF = heart failure.

Class of recommendation.

Level of evidence.

Open in new tab

9.8 CHRONIC KIDNEY DISEASE

CKD is defined as abnormalities of kidney structure or function, present for >3
months, with implications for health. CKD is classified on the basis of the
cause, GFR category, and category of albuminuria.488 In the adult population,
decreasing GFR is associated with increased CVD risk, independent of other CV
risk factors.489–492 There is an increased risk of both atherosclerotic vascular
disease and structural heart disease.492 Patients with CKD and established CVD
have a much higher mortality rate compared with patients with CVD and normal
renal function.493 Therefore, patients with CKD are considered to be at high
(stage 3 CKD) or very-high risk (stage 4–5 CKD or on dialysis) of CVD, and there
is no need to use risk estimation models in these patients.

9.8.1 LIPOPROTEIN PROFILE IN CHRONIC KIDNEY DISEASE

In the initial stages of CKD, TG levels are specifically elevated and HDL-C
levels are lowered. LDL subclasses display a shift to an excess of small dense
LDL particles. Studies suggest that the kidney has a role in Lp(a) catabolism
and that Lp(a) levels are increased in association with kidney disease. Such
acquired abnormalities can be reversed by kidney transplantation or remission of
nephrosis.

9.8.2 EVIDENCE FOR RISK REDUCTION THROUGH STATIN-BASED THERAPY IN PATIENTS WITH
CHRONIC KIDNEY DISEASE

In the Die Deutsche Diabetes Dialyse Studie (4D) trial, which involved 1200
patients with diabetes on haemodialysis, atorvastatin had no significant effect
on risk of CVD.220 Similar results were obtained in the AURORA (A study to
evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an
Assessment of survival and cardiovascular events) trial, which involved 2776
patients on haemodialysis.221

In the SHARP study,222 simvastatin and ezetimibe combination therapy reduced the
risk for major atherosclerotic events (coronary death, MI, non-haemorrhagic
stroke, or any revascularization) compared with placebo in persons with CKD
stage 3A–5. The trial did not have sufficient power to separately assess the
effects on the primary outcome in dialysis and non-dialysis patients. Although
statin-based therapy is clearly effective in mild-to-moderate CKD, a major
controversy that remained after the publication of the 4D, AURORA, and SHARP
studies was whether statin therapy is effective in more advanced CKD,
particularly dialysis patients. By combining data from the three CKD trials with
other trials in the existing database, the CTT investigators found that, even
after adjusting for the smaller LDL-C reductions achieved among patients with
more advanced CKD and for differences in outcome definitions between dialysis
trials, there was a trend towards smaller relative reductions per mmol/L
reduction in LDL-C in major atherosclerotic events as estimated GFR (eGFR)
declines (with little evidence of benefit among dialysis patients).214 This
diminution in relative risk reduction as GFR declines implies that, at least in
non-dialysis patients, more intensive LDL-lowering regimens are required to
achieve the same benefit.

9.8.3 SAFETY OF LIPID MANAGEMENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Safety issues and dose adjustments are important in advanced stages of CKD
(stages 3–5), as adverse events are commonly dose-related and due to increased
blood concentrations of compounds. Although it has been suggested that
preference should be given to regimens and doses that have been shown to be
beneficial in RCTs conducted specifically in such patients,494 the CTT
meta-analysis makes clear that the goal—as in patients without CKD—should be to
achieve the largest possible absolute reduction in LDL-C safely. Although there
were no specific safety concerns raised by the 4D, AURORA, or SHARP trials,
statins metabolized via CYP3A4 may result in adverse effects due to drug–drug
interactions and caution is required.

Based on the evidence for lipid management in patients with CKD, the Kidney
Disease: Improving Global Outcomes (KDIGO) organization has developed an updated
clinical practice guideline for lipid management in CKD.494 In line with this,
but with a focus on those patients at high or very-high risk for developing CVD,
recommendations are summarized below.

Recommendations for lipid management in patients with moderate-to-severe (Kidney
Disease Outcomes Quality Initiative stages 3–5) chronic kidney disease

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease;
eGFR = estimated glomerular filtration rate.

Class of recommendation.

Level of evidence.

Defined as eGFR < 60ml/min/1.73m2 on two measurements more than 3 months apart.

Open in new tab

Recommendations for lipid management in patients with moderate-to-severe (Kidney
Disease Outcomes Quality Initiative stages 3–5) chronic kidney disease

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease;
eGFR = estimated glomerular filtration rate.

Class of recommendation.

Level of evidence.

Defined as eGFR < 60ml/min/1.73m2 on two measurements more than 3 months apart.

Open in new tab

9.9 TRANSPLANTATION

Dyslipidaemias are very common in patients who have undergone heart, lung,
liver, kidney, or allogenic haematopoietic stem cell transplantation, and
predispose such patients to an increased risk of developing ASCVD and transplant
arterial vasculopathy.497–501 In patients with CKD undergoing renal
transplantation, the risk of ASCVD may be determined, at least in part, by the
increased risk resulting from CKD itself.

Immunosuppressive drug regimens may have adverse effects on lipid metabolism
leading to increases in TC, VLDL, and TGs, and in the size and density of LDL
particles. These effects vary with different immunosuppressive
drugs.497,498,502–506

The management of dyslipidaemias in transplant recipients is comparable to what
is recommended for patients at high or very high ASCVD risk, although more
attention is needed regarding the causes of the lipid disturbances and possible
side effects due to drug–drug interactions (see Recommendations for low-density
lipoprotein in solid organ transplant patients below).

The clinical effectiveness of statins in renal transplant patients is uncertain
owing to a lack of randomized trials in this population. A systematic review of
the benefits and harms of statins in patients with a functioning kidney
transplant included 3465 patients, free of CHD, from 22 studies. Although the
authors concluded that statins may reduce CV events, they also suggested a need
for additional studies.253 However, in patients with a functioning renal
transplant at increased risk of CVD, it may be appropriate to extrapolate from
the clear evidence of benefit from statin therapy, without safety concerns, in
people with moderate reductions in GFR.214

Several potential drug interactions must also be considered, especially with
ciclosporin, which is metabolized through CYP3A4, and may increase systemic
statin exposure and the risk of myopathy. Ciclosporin increases the blood levels
of all statins.

Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized through
different CYP enzymes than the others and have less potential for
interaction.507

Tacrolimus is also metabolized by CYP3A4, but appears to have less potential for
harmful interaction with statins than ciclosporin. Other drugs that influence
CYP3A4 activity should be avoided if possible, and used with extreme caution in
patients receiving both calcineurin inhibitors and statins.

For transplant patients with dyslipidaemia, ezetimibe could be considered as an
alternative for patients unable to take a statin or added to the highest
tolerated statin dose.507–509 No outcome data are available for this drug, which
should generally be reserved for second-line use. Ciclosporin can induce a
2–12-fold increase in the ezetimibe level.

Care is required with the use of fibrates, as they can decrease ciclosporin
levels and have the potential to cause myopathy. Extreme caution is required if
fibrate therapy is planned in combination with a statin. Cholestyramine is not
effective as monotherapy in heart transplant patients and has the potential to
reduce absorption of immunosuppressants; this potential is minimized by separate
administration.

Recommendations for low-density lipoprotein lowering in solid organ transplant
patients

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for low-density lipoprotein lowering in solid organ transplant
patients

Class of recommendation.

Level of evidence.

Open in new tab

9.10 PERIPHERAL ARTERIAL DISEASE

PAD encompasses all vascular sites, including carotid, vertebral, upper
extremity, mesenteric, renal, and lower extremity arteries. The aorta is often
included in the term.510 PAD is a common manifestation of atherosclerosis and
such patients are at elevated risk of coronary events, with PAD representing an
independent risk factor for MI and CV death.510,511 Patients with PAD are at
very-high risk and should be managed according to the recommendations in
Table 7. Elevated CV risk has led to the inclusion of PAD among the list of
‘risk equivalent’ conditions, and therapeutic strategies of secondary prevention
should be implemented [see Recommendations for lipid-lowering drugs in patients
with peripheral arterial disease (including carotid artery disease) below]. Yet,
despite the high CV morbidity and mortality risk, PAD patients are usually
inadequately managed compared with CAD patients.511

9.10.1 LOWER EXTREMITY ARTERIAL DISEASE

A low ABI (0.90) is diagnostic for lower extremity arterial disease (LEAD).
Either a low (0.90) or high (1.40, related to stiffened arteries) ABI is
predictive of CV morbidity and mortality. Lowering LDL-C levels reduces the risk
of ischaemic CV events and worsening of claudication, while it also improves
walking performance. As for cardiac events, a systematic review of 18 trials
including 10 000 patients, with cholesterol levels ranging from normal to
elevated, reported that lipid-lowering therapy in people affected by
atherosclerosis of the lower limbs was associated with a 20% reduction in total
CV events, together with a non-significant 14% reduction of all-cause
mortality.512 In the Heart Protection Study, the need for non-coronary
revascularization was reduced by 16% with statin therapy.513

In addition to statins, PSCK9 inhibitors have also been shown to reduce CV
events in PAD patients. In a pre-specified subgroup analysis of the FOURIER
trial, evolocumab significantly reduced the primary endpoint in patients with
PAD.514 PAD had larger absolute risk reductions for the primary endpoint (3.5%
with PAD and 1.6% without PAD). Evolocumab also reduced the risk of major
adverse limb events by 42% in patients, with consistent effects in those with
and without known PAD. In the FIELD trial, fenofibrate reduced the risk of
amputations, particularly minor amputations without known large-vessel disease,
probably through non-lipid mechanisms.515

9.10.2 CAROTID ARTERY DISEASE

While there are currently no randomized studies that have assessed whether
lipid-lowering treatments reduce the incidence of CV events in patients enrolled
on the basis of carotid atherosclerotic disease and without previous CV events,
lipid-lowering therapy had reduced stroke in numerous studies. In a
meta-analysis of RCTs enrolling >90 000 patients, statin therapy did lead to a
21% reduction in the incidence of all strokes in different populations; this
effect was mainly driven by the extent of LDL-C reduction.460

9.10.3 RETINAL VASCULAR DISEASE

Atherosclerotic changes of retinal arteries correlate with TC, LDL-C, TG, and
apoB levels and also with CAD.516 Fenofibrate reduces the progression of
diabetic retinopathy.517,518

9.10.4 SECONDARY PREVENTION IN PATIENTS WITH ABDOMINAL AORTIC ANEURYSM

The presence of an abdominal aortic aneurysm represents a risk-equivalent
condition for CAD and is associated with age, male gender, personal history of
atherosclerotic CVD, smoking, hypertension, and dyslipidaemia;519 in contrast,
diabetic patients are at decreased risk.

There are currently no available clinical trials on the reduction of CV risk
with lipid-lowering therapy in patients affected by this condition. Systematic
reviews,520 mostly based on retrospective non-randomized studies, have reported
that there is still inconclusive evidence that statin therapy reduces
peri-operative CV morbidity and mortality. In an RCT comparing atorvastatin 20
mg with placebo, the composite endpoint of cardiac death, MI, stroke, and
unstable angina was significantly reduced in 100 patients undergoing vascular
non-cardiac surgery, including abdominal aortic aneurysm repair.521 In another
double-blind, placebo-controlled trial in 497 patients undergoing vascular
surgery, peri-operative fluvastatin therapy (80 mg/day) was associated with an
improvement in post-operative cardiac outcome.522

9.10.5 RENOVASCULAR ATHEROSCLEROSIS

Lipid-lowering therapy has never been tested in an RCT in patients affected by
renovascular atherosclerosis; however, a recent non-randomized population-based
study showed that in patients older than 65 years of age with atherosclerotic
renovascular disease raised the hypothesis that such treatment may yield
cardiorenal benefits; the risk of a major cardiorenal composite endpoint (MI,
stroke, HF, acute renal failure, dialysis, and death) was significantly lower in
statin users than in non-users.523

Recommendations for lipid-lowering drugs in patients with peripheral arterial
disease (including carotid artery disease)

ASCVD = atherosclerotic cardiovascular disease; PAD = peripheral arterial
disease; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

Open in new tab

Recommendations for lipid-lowering drugs in patients with peripheral arterial
disease (including carotid artery disease)

ASCVD = atherosclerotic cardiovascular disease; PAD = peripheral arterial
disease; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Class of recommendation.

Level of evidence.

Open in new tab

9.11 OTHER SPECIAL POPULATIONS AT RISK OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

In general, the effects of lowering LDL-C are determined by the absolute risk of
ASCVD and the achieved reduction in LDL-C, so it is important to identify and
treat all those at increased risk of ASCVD. There are a few specific groups of
patients in whom an underlying disease confers such increased risk, and in
addition in whom the standard treatments may themselves cause dyslipidaemia that
may contribute to the risk of ASCVD. These include: (i) chronic immune-mediated
inflammatory disease, (ii) patients with human immunodeficiency virus (HIV), and
(iii) patients with severe mental illness. The management principles are the
same in these patient groups, but their management may need to address specific
issues related to individual dyslipidaemias and drug safety. Details are
provided in the Supplementary Data document.

10 INFLAMMATION

Recent advances in basic science have established a fundamental role for
low-degree chronic inflammation in mediating all stages of atherosclerosis, from
initiation through progression and, ultimately, to the rupture of plaque and
ensuing thrombotic complications of atherosclerosis. The cellular and molecular
interactions involved during atherogenesis are fundamentally not different from
those in chronic inflammatory–fibroproliferative diseases, such as rheumatoid
arthritis (RA), glomerulosclerosis, or pulmonary fibrosis.525 Almost all cell
types of the immuno-inflammatory system, such as macrophages, and T- and
B-cells, as well as many pro- and anti-inflammatory cytokines and chemokines,
have been identified during the process of atherosclerosis.526

Interestingly, cholesterol accumulation in cells triggers the inflammasome
response and results in the production of inflammatory mediators such as
interleukin (IL)-1β. Numerous animal studies, using the knockout model, have
demonstrated that inflammation and the immune system both play crucial roles
during atherogenesis.527

During inflammatory processes, large numbers of acute-phase proteins have been
identified, and several clinical studies have reported C-reactive protein528 to
be the most useful serum marker of inflammation, even though it has poor
specificity for any particular inflammation process, including atherosclerosis.
The high-sensitivity C-reactive protein diagnostic test was developed to detect
very low levels of C-reactive protein, and thereby enable a more accurate and
precise measure of chronic inflammation compared with standard C-reactive
protein.529 This diagnostic tool differs only in the range of C-reactive protein
levels that it can detect. Several studies have found that elevated levels of
high-sensitivity C-reactive protein in the blood are associated with an
increased risk of CV events and could be used to predict clinical outcomes
independently of cholesterol levels.530,531 Other studies have not been able to
show any relationship between low-grade chronic inflammation, as indicated by
high-sensitivity C-reactive protein levels, and increased risk of CV.532–535
Finally, genetic studies of large population cohorts have not demonstrated that
chronic elevated high-sensitivity C-reactive protein increases the risk of
atherosclerotic events.536 Nevertheless, in some guidelines, high-sensitivity
C-reactive protein has been added to traditional risk factors for prognostic
information, especially for patients at intermediate risk.537,538

Statins have been shown to reduce C-reactive protein secretion by
hepatocytes,539 and a series of clinical trials and post hoc analyses have found
that beneficial outcomes after statin therapy relate both to a reduction in
cholesterol levels and reduced inflammation.540–544 The Justification for the
Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) trial542 demonstrated that in primary prevention for individuals with
chronically elevated C-reactive protein (>2 mg/L), statin treatment markedly
reduced CV events.545 It is of note that other lipid-lowering agents, such as
ezetimibe and more recently the anti-PCSK9 mAbs, do not influence
high-sensitivity C-reactive protein levels,546,547 but lead to further
significant reductions in CV events when added to statin therapy.

Specific anti-inflammatory treatment was tested in the Canakinumab
Antiinflammatory Thrombosis Outcome Study (CANTOS) trial.548 In patients with
previous MI and chronic elevated high-sensitivity C-reactive protein levels, all
on optimal medical treatment, including statins, the anti-IL-1β mAb canakinumab
dose-dependently reduced high-sensitivity C-reactive protein and significantly
lowered the rate of recurrent CV events compared with placebo, independently of
the level of lipid lowering. Not surprisingly, there was a slight increase in
the risk of severe and fatal infections associated with canakinumab. This study
was the first to highlight the positive correlation between high-sensitivity
C-reactive protein and CV events, where lower achieved high-sensitivity
C-reactive protein values were directly correlated with a lower risk of future
CV events.548 Nevertheless, the FDA declined to approve canakinumab for CV risk
reduction on the strength of data from the CANTOS study. As canakinumab
treatment has not been tested against anti-PCSK9 mAb and/or ezetimibe added to
statin therapy, the question of residual risk remains for patients with elevated
high-sensitivity C-reactive protein despite achieving very low (below goal)
LDL-C values, and whether patients with very low LDL-C would benefit from
anti-IL-1β treatment or other anti-inflammatory agents. In addition, all
currently recommended lipid-lowering drugs, including anti-PCSK9 mAbs, have
demonstrated beneficial effects on atherosclerotic plaque composition as well as
plaque volume regression; such results are still missing for anti-inflammatory
treatment. Another anti-inflammatory approach using methotrexate was tested in
the Cardiovascular Inflammation Reduction Trial (CIRT).549 Very low-dose
methotrexate (10 mg weekly), a proven anti-inflammatory regimen that reduces
tumour necrosis factor (TNF), IL-6, and C-reactive protein levels and is widely
used in the treatment of RA, was allocated vs. placebo to 7000 stable CAD
patients. This study was stopped prematurely due to futility. Interestingly,
this regimen of methotrexate had no effect on either IL-6 or high-sensitivity
C-reactive protein blood levels in this population, which could explain the
neutral results of this trial.550 Based on the current level of evidence, no
further recommendations on the use of anti-inflammatory agents can be made.551

11 MONITORING OF LIPIDS AND ENZYMES IN PATIENTS ON LIPID-LOWERING THERAPY

Evidence concerning which tests should be carried out to monitor lipids in
patients on treatment is limited. Similar limited evidence applies to tests of
possible toxicity, such as ALT and CK. Recommendations stem from consensus
rather than evidence-based medicine.

Response to therapy can be assessed at 6–8 weeks from initiation of therapy, but
response to lifestyle may take longer. Standard practice for subsequent
follow-up monitoring is 6–12 months, but such monitoring intervals are
arbitrary. As a minimum, LDL-C should be assessed whenever available, but better
management decisions will probably occur if a full lipid profile is performed,
including HDL-C and TGs. Non-HDL-C or ApoB should also be analysed, and used as
a secondary treatment target. A separate issue is the impact of regular lipid
monitoring in promoting patient adherence to lifestyle changes or drug regimens
that impact positively on their health, as found in a range of studies. It is
unclear whether only the process of monitoring is critical in achieving this or
whether a combination of education, regular contact, and adherence assessment is
required.

Where pharmacological lipid-lowering therapy is implemented, safety blood tests
are advised, including ALT and CK at baseline, to identify the limited number of
patients where treatment is contraindicated. CK should be checked in patients at
high-risk for myopathy, such as the very elderly with comorbidities, patients
with antecedents of muscle symptoms, or patients receiving interacting drugs. A
mild and typically transient elevation of ALT is seen in about 2% of patients
and normalization is seen with continuing therapy.240,244,552 Recent reviews are
encouraging regarding the safety of long-term statin therapy and statin-induced
liver injury is reported to be very uncommon.243,244,553–555 ALT is recommended
before the start of statin therapy; routine control of ALT during treatment is
not recommended but should be performed, if indicated, based on clinical
observations. During fibrate therapy, regular ALT control is still recommended.
In patients whose liver function tests increase to above three times the ULN,
explanations such as alcohol ingestion or NAFLD should be sought, and the levels
monitored. If levels remain elevated then lipid-lowering therapy should be
stopped, but may be cautiously reintroduced under monitoring after levels have
returned to normal.

There is no predictive value of routine repeat CK testing for rhabdomyolysis
since the level can increase for many reasons, including muscle injury or excess
muscular exercise. However, CK must be assessed immediately in patients who
present with muscle pain and weakness, and especially in the elderly, and
treatment stopped if CK rises to >10 times the ULN. Strategies to handle CK
elevations are given in Table 13.

Due to the increased frequency of DM during statin treatment,247,249,556,557
regular checks of HbA1c should be considered in patients at high-risk of
developing DM and under high-dose statin treatment. Groups to be considered for
glucose control are the elderly or those with MetS, obesity, or signs of insulin
resistance.

Table 13

Summary of recommendations for monitoring lipids and enzymes in patients, before
and on lipid-lowering therapy

Testing lipids How often should lipids be tested?

* Before starting lipid-lowering drug treatment, at least two measurements
should be made, with an interval of 1–12 weeks, with the exception of
conditions where prompt drug treatment is suggested, such as ACS and very
high-risk patients.

How often should a patient’s lipids be tested after starting lipid-lowering
treatment?

* After starting treatment: 8 (±4) weeks.

* After adjustment of treatment: 8 (±4) weeks until the goal is achieved.

How often should lipids be tested once a patient has achieved the target or
optimal lipid level?

* Annually (unless there are adherence problems or other specific reasons for
more frequent reviews).

Monitoring liver and muscle enzymes How often should liver enzymes (ALT) be
routinely measured in patients on lipid-lowering drugs?

* Before treatment.

* Once, 8–12 weeks after starting a drug treatment or after dose increase.

* Routine control of ALT thereafter is not recommended during statin treatment,
unless symptoms suggesting liver disease evolve. During treatment with
fibrates, control of ALT is still recommended.

What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3× ULN:

* Continue therapy.

* Recheck liver enzymes in 4–6 weeks.

If ALT rises to ≥3× ULN

* Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within
4–6 weeks.

* Cautious reintroduction of therapy may be considered after ALT has returned
to normal.

* If ALT remains elevated check for the other reasons.

How often should CK be measured in patients taking lipid-lowering drugs?

* Pre-treatment

* Before starting therapy.

* If baseline CK is >4× ULN, do not start drug therapy; recheck.

* Monitoring:

* Routine monitoring of CK is not necessary.

* Check CK if patient develops myalgia.

Be alert regarding myopathy and CK elevation in patients at risk, such as:
elderly patients, those on concomitant interfering therapy, multiple
medications, liver or renal disease, or athletes. What if CK becomes elevated in
a person taking lipid-lowering drugs? Re-evaluate indication for statin
treatment. If ≥4× ULN:

* If CK >10× ULN: stop treatment, check renal function, and monitor CK every 2
weeks.

* If CK <10× ULN: if no symptoms, continue lipid-lowering therapy while
monitoring CK between 2 and 6 weeks.

* If CK <10× ULN: if symptoms present, stop statin and monitor normalization of
CK, before rechallenge with a lower statin dose.

* Consider the possibility of transient CK elevation for other reasons such as
exertion.

* Consider myopathy if CK remains elevated.

* Consider combination therapy or an alternative drug.

If <4× ULN:

* If no muscle symptoms, continue statin (patient should be alerted to report
symptoms; check CK).

* If muscle symptoms, monitor symptoms and CK regularly.

* If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks;
re-evaluate indication for statin treatment.

* Consider rechallenge with the same or another statin.

* Consider low-dose statin, alternate day or once/twice weekly dosing regimen,
or combination therapy.

For details on CK elevation and treatment of muscular symptoms during statin
treatment see algorithm in Supplementary Figure 4. In which patients should
HbA1c or blood glucose be checked?

* Regular checks of HbA1c or glucose should be considered in patients at
high-risk of developing diabetes, and on high-dose statin treatment.

* Groups to be considered for glucose control are the elderly and patients with
metabolic syndrome, obesity, or other signs of insulin resistance.

Testing lipids How often should lipids be tested?

How often should a patient’s lipids be tested after starting lipid-lowering
treatment?

* After starting treatment: 8 (±4) weeks.

* After adjustment of treatment: 8 (±4) weeks until the goal is achieved.

How often should lipids be tested once a patient has achieved the target or
optimal lipid level?

* Annually (unless there are adherence problems or other specific reasons for
more frequent reviews).

Monitoring liver and muscle enzymes How often should liver enzymes (ALT) be
routinely measured in patients on lipid-lowering drugs?

* Before treatment.

* Once, 8–12 weeks after starting a drug treatment or after dose increase.

* Routine control of ALT thereafter is not recommended during statin treatment,
unless symptoms suggesting liver disease evolve. During treatment with
fibrates, control of ALT is still recommended.

What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3× ULN:

* Continue therapy.

* Recheck liver enzymes in 4–6 weeks.

If ALT rises to ≥3× ULN

* Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within
4–6 weeks.

* Cautious reintroduction of therapy may be considered after ALT has returned
to normal.

* If ALT remains elevated check for the other reasons.

How often should CK be measured in patients taking lipid-lowering drugs?

* Pre-treatment

* Before starting therapy.

* If baseline CK is >4× ULN, do not start drug therapy; recheck.

* Monitoring:

* Routine monitoring of CK is not necessary.

* Check CK if patient develops myalgia.

* If CK >10× ULN: stop treatment, check renal function, and monitor CK every 2
weeks.

* If CK <10× ULN: if no symptoms, continue lipid-lowering therapy while
monitoring CK between 2 and 6 weeks.

* If CK <10× ULN: if symptoms present, stop statin and monitor normalization of
CK, before rechallenge with a lower statin dose.

* Consider the possibility of transient CK elevation for other reasons such as
exertion.

* Consider myopathy if CK remains elevated.

* Consider combination therapy or an alternative drug.

If <4× ULN:

* If no muscle symptoms, continue statin (patient should be alerted to report
symptoms; check CK).

* If muscle symptoms, monitor symptoms and CK regularly.

* If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks;
re-evaluate indication for statin treatment.

* Consider rechallenge with the same or another statin.

* Consider low-dose statin, alternate day or once/twice weekly dosing regimen,
or combination therapy.

For details on CK elevation and treatment of muscular symptoms during statin
treatment see algorithm in Supplementary Figure 4. In which patients should
HbA1c or blood glucose be checked?

* Regular checks of HbA1c or glucose should be considered in patients at
high-risk of developing diabetes, and on high-dose statin treatment.

* Groups to be considered for glucose control are the elderly and patients with
metabolic syndrome, obesity, or other signs of insulin resistance.

ACS = acute coronary syndrome; ALT = alanine aminotransferase; CK = creatine
kinase; ULN = upper limit of normal.

Open in new tab
Table 13

Summary of recommendations for monitoring lipids and enzymes in patients, before
and on lipid-lowering therapy

Testing lipids How often should lipids be tested?

How often should a patient’s lipids be tested after starting lipid-lowering
treatment?

* After starting treatment: 8 (±4) weeks.

* After adjustment of treatment: 8 (±4) weeks until the goal is achieved.

How often should lipids be tested once a patient has achieved the target or
optimal lipid level?

* Annually (unless there are adherence problems or other specific reasons for
more frequent reviews).

Monitoring liver and muscle enzymes How often should liver enzymes (ALT) be
routinely measured in patients on lipid-lowering drugs?

* Before treatment.

* Once, 8–12 weeks after starting a drug treatment or after dose increase.

* Routine control of ALT thereafter is not recommended during statin treatment,
unless symptoms suggesting liver disease evolve. During treatment with
fibrates, control of ALT is still recommended.

What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3× ULN:

* Continue therapy.

* Recheck liver enzymes in 4–6 weeks.

If ALT rises to ≥3× ULN

* Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within
4–6 weeks.

* Cautious reintroduction of therapy may be considered after ALT has returned
to normal.

* If ALT remains elevated check for the other reasons.

How often should CK be measured in patients taking lipid-lowering drugs?

* Pre-treatment

* Before starting therapy.

* If baseline CK is >4× ULN, do not start drug therapy; recheck.

* Monitoring:

* Routine monitoring of CK is not necessary.

* Check CK if patient develops myalgia.

* If CK >10× ULN: stop treatment, check renal function, and monitor CK every 2
weeks.

* If CK <10× ULN: if no symptoms, continue lipid-lowering therapy while
monitoring CK between 2 and 6 weeks.

* If CK <10× ULN: if symptoms present, stop statin and monitor normalization of
CK, before rechallenge with a lower statin dose.

* Consider the possibility of transient CK elevation for other reasons such as
exertion.

* Consider myopathy if CK remains elevated.

* Consider combination therapy or an alternative drug.

If <4× ULN:

* If no muscle symptoms, continue statin (patient should be alerted to report
symptoms; check CK).

* If muscle symptoms, monitor symptoms and CK regularly.

* If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks;
re-evaluate indication for statin treatment.

* Consider rechallenge with the same or another statin.

* Consider low-dose statin, alternate day or once/twice weekly dosing regimen,
or combination therapy.

For details on CK elevation and treatment of muscular symptoms during statin
treatment see algorithm in Supplementary Figure 4. In which patients should
HbA1c or blood glucose be checked?

* Regular checks of HbA1c or glucose should be considered in patients at
high-risk of developing diabetes, and on high-dose statin treatment.

* Groups to be considered for glucose control are the elderly and patients with
metabolic syndrome, obesity, or other signs of insulin resistance.

Testing lipids How often should lipids be tested?

How often should a patient’s lipids be tested after starting lipid-lowering
treatment?

* After starting treatment: 8 (±4) weeks.

* After adjustment of treatment: 8 (±4) weeks until the goal is achieved.

How often should lipids be tested once a patient has achieved the target or
optimal lipid level?

* Annually (unless there are adherence problems or other specific reasons for
more frequent reviews).

Monitoring liver and muscle enzymes How often should liver enzymes (ALT) be
routinely measured in patients on lipid-lowering drugs?

* Before treatment.

* Once, 8–12 weeks after starting a drug treatment or after dose increase.

* Routine control of ALT thereafter is not recommended during statin treatment,
unless symptoms suggesting liver disease evolve. During treatment with
fibrates, control of ALT is still recommended.

What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3× ULN:

* Continue therapy.

* Recheck liver enzymes in 4–6 weeks.

If ALT rises to ≥3× ULN

* Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within
4–6 weeks.

* Cautious reintroduction of therapy may be considered after ALT has returned
to normal.

* If ALT remains elevated check for the other reasons.

How often should CK be measured in patients taking lipid-lowering drugs?

* Pre-treatment

* Before starting therapy.

* If baseline CK is >4× ULN, do not start drug therapy; recheck.

* Monitoring:

* Routine monitoring of CK is not necessary.

* Check CK if patient develops myalgia.

* If CK >10× ULN: stop treatment, check renal function, and monitor CK every 2
weeks.

* If CK <10× ULN: if no symptoms, continue lipid-lowering therapy while
monitoring CK between 2 and 6 weeks.

* If CK <10× ULN: if symptoms present, stop statin and monitor normalization of
CK, before rechallenge with a lower statin dose.

* Consider the possibility of transient CK elevation for other reasons such as
exertion.

* Consider myopathy if CK remains elevated.

* Consider combination therapy or an alternative drug.

If <4× ULN:

* If no muscle symptoms, continue statin (patient should be alerted to report
symptoms; check CK).

* If muscle symptoms, monitor symptoms and CK regularly.

* If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks;
re-evaluate indication for statin treatment.

* Consider rechallenge with the same or another statin.

* Consider low-dose statin, alternate day or once/twice weekly dosing regimen,
or combination therapy.

For details on CK elevation and treatment of muscular symptoms during statin
treatment see algorithm in Supplementary Figure 4. In which patients should
HbA1c or blood glucose be checked?

* Regular checks of HbA1c or glucose should be considered in patients at
high-risk of developing diabetes, and on high-dose statin treatment.

* Groups to be considered for glucose control are the elderly and patients with
metabolic syndrome, obesity, or other signs of insulin resistance.

ACS = acute coronary syndrome; ALT = alanine aminotransferase; CK = creatine
kinase; ULN = upper limit of normal.

Open in new tab

12 COST-EFFECTIVENESS OF CARDIOVASCULAR DISEASE PREVENTION BY LIPID MODIFICATION

In 2015, there were >85 million people in Europe living with CVD.558 Aging
populations,559 unhealthy diets, smoking, sedentary lifestyles, increasing
obesity, and diabetes560–563 are the main contributors. CVD cost the European
Union about €210 billion in 2015, one-half of which was in healthcare costs (∼8%
of total healthcare expenditure), and the other half in productivity losses and
informal care.558

In these Guidelines, the Joint Task Force recommends a range of actions to
reduce CVD by targeting plasma lipids, ranging from population-wide initiatives
to promote healthy lifestyles to individual-level interventions to reduce CVD
risk factors, such as unhealthy diets and high lipid levels. Cost-effectiveness
analysis can help target resources for interventions where the net health gain
is greatest in relation to the net resources, and is increasingly required
across Europe.564 However, cost-effectiveness depends on available resources,
the costs of services, and disease risk in the population, and results obtained
in one country might not be valid in another.565 In addition, to fully capture
the long-term effects of interventions, cost-effectiveness studies combining
evidence from RCTs with modelling and limitations in both could affect the
reliability of findings. Here, the evidence for the cost-effectiveness of ASCVD
preventive interventions with respect to lipid modification is summarized;
further scrutiny in view of local circumstances is recommended.

The health impact pyramid summarizes the evidence on the relative effort in
relation to health impact (Figure 5), with interventions with the broadest
impact on populations at the base and interventions requiring considerable
individual effort at the top.566 There is consensus that all the levels of the
pyramid should be targeted but that emphasis should be placed on the lower
levels. This would address the persistent socio-economic divide in CV health
despite major improvements in ASCVD treatment.558

Figure 5
Open in new tabDownload slide

Health impact pyramid.

More than one-half of the reduction in CV mortality over the last three decades
has been attributed to population-level changes in CV risk factors, primarily
reductions in plasma cholesterol, BP levels, and smoking.560–563,567 Lifestyle
changes at the population level may be more cost-effective than lifestyle and
drug interventions at the individual level, particularly when targeted to
populations at increased risk. Awareness and knowledge of how lifestyle risk
factors lead to CVD has increased in recent decades. Moreover, legislation
promoting a healthy lifestyle, such as reduced salt intake and smoking bans, has
been reported to be cost-effective in preventing CVD,568–573 and initiatives to
improve infrastructure and promote physical activity have shown promise.574,575
A number of structural strategies at international, national, and regional
levels combined can substantially reduce CVD morbidity and mortality.576,577
Individual-level interventions to improve diet,578,579 increase physical
activity,580 and stop smoking581 could also be cost-effective.582 However,
suboptimal adherence limits benefits,583,584 and interventions to improve
adherence, such as electronic device reminders to reinforce favourable health
behaviours, are increasingly being investigated.585

All statin regimens and ezetimibe are now generically available across Europe.
There is strong evidence that lowering blood cholesterol levels using low-cost
statins is widely cost-effective586–590 in many categories of patients. For
secondary prevention of CVD, the evidence suggests that statin treatments are
highly cost-effective,586,590,591 and adding low-cost ezetimibe to
high-intensity statin therapy further reduces LDL-C and CVD risk
cost-effectively.592 In primary ASCVD prevention, the evidence indicates that
generic statin-based treatments are cost-effective for people at least down to
1% annual total CVD risk and could be cost-effective at even lower risk,589 with
the highest tolerated statin dose likely the most cost-effective.591,593,594
Importantly, many patients on statin treatment fail to take their medications
adequately and/or to reach their therapeutic goals,595 with clinical and
economic consequences.596,597 Reinforcing measures aimed at improving adherence
to treatment is cost-effective.598–600

Studies have shown that at mid-2018 prices PCSK9 inhibitors were largely not
cost-effective.601–604 Their cost-effectiveness is improved in selected
high-risk patients, such as those with clinical CVD or FH, other comorbidities,
and high LDL-C levels.605,606 However, at lower prices, PCSK9 inhibitors would
become cost-effective in a wider range of high-risk patients; recent price
reductions may therefore lead to increased use.607 Cost-effectiveness evidence
for other lipid-modifying therapies is lacking.

Effective interventions to prevent ASCVD, including statins, typically exhibit
similar relative risk reductions across categories of patients, including by
ASCVD risk; therefore, health benefits and cost-effectiveness are greater among
people at higher ASCVD risk (Figure 6).36,233 Consequently, increased efforts
and higher-intensity interventions should be aimed at individuals and
populations at higher ASCVD risk.

Figure 6
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Absolute reductions in major vascular events with statin therapy.233 LDL =
low-density lipoprotein. Reproduced from The Lancet, 388/10059, Collins et al.,
‘Interpretation of the evidence for the efficacy and safety of statin therapy’,
2532-2561, 2016, with permission from Elsevier.

Box 8 lists the key messages regarding the cost-effectiveness of CVD prevention
by lipid modification, and Box 9 highlights gaps in the evidence.

Box 8

Key messages

Prevention of CVD by lifestyle changes, medication, or both is cost-effective in
many scenarios, including population-based approaches and actions directed at
individuals at increased CVD risk. Cost-effectiveness depends on several
factors, including baseline CVD risk and LDL levels, cost of treatment, and
uptake of preventive strategies. Interventions to prevent CVD are more
cost-effective among individuals and populations at higher CVD
risk. Cost-effectiveness analyses are importantly informed by assumptions about
long-term disease prognosis and treatment effects. Strengthening of the evidence
to inform these assumptions is encouraged.

CVD = cardiovascular disease; LDL = low-density lipoprotein.

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Box 8

Key messages

CVD = cardiovascular disease; LDL = low-density lipoprotein.

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Box 9

Gaps in the evidence

Cost-effectiveness requires evidence for effects of interventions on health and
healthcare over a long time period; modelling techniques fill gaps. More data
are needed from RCTs and observational studies. Direct evidence of effects of
lipid-modifying treatments on overall mortality, particularly among people at
low-to-moderate CVD risk, older people, and for newer interventions, is lacking.
Long-term post-trial follow-up in RCTs should be encouraged. The
cost-effectiveness of using lifetime CVD risk and more precise CVD risk scores
to target interventions needs further investigation.

CVD = cardiovascular disease; RCT = randomized controlled trial.

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Box 9

Gaps in the evidence

CVD = cardiovascular disease; RCT = randomized controlled trial.

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13 STRATEGIES TO ENCOURAGE ADOPTION OF HEALTHY LIFESTYLE CHANGES AND ADHERENCE
TO LIPID-MODIFYING THERAPIES

Helping patients to change to healthier lifestyle habits is most effectively
achieved through formal programmes of preventive care, possibly because of the
intensive follow-up and multidisciplinary expertise they provide.608 However, in
everyday care, adherence to both healthy lifestyle changes and medication
regimens is a challenge to patients and professionals.

A comprehensive patient- and family-centred approach located in one healthcare
setting is recommended rather than addressing single risk factors with more than
one intervention in different locations. Box 10 includes some useful techniques
when counselling patients for behavioural change.

A comprehensive approach to improving adherence to medication is described in
the Supplementary Data document.

Box 10

Methods for enhancing adherence to lifestyle changes

1. Explore motivation and identify ambivalence. Weigh pros and cons for change,
assess and build self-efficacy and confidence, and avoid circular discussion. 2.
Offer support, and establish an alliance with the patient and his/her family. 3.
Involve the partner, other household members, or caregiver who may be
influential in the lifestyle of the patient. 4. Use the OARS method (Open-ended
questions, Affirmation, Reflective listening, Summarising when discussing
behaviour changes
(www.smartrecovery.org/wp-content/uploads/2017/03/UsingMIinSR.pdf). 5. Tailor
advice to an individual patient’s culture, habits, and situation. 6. Use SMART
goal setting (negotiate goals for change that are Specific, Measurable,
Achievable, Realistic, and Timely). Follow-up on goals and record progress on a
shared record.

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Box 10

Methods for enhancing adherence to lifestyle changes

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14 KEY MESSAGES

1. Cholesterol and risk. Prospective studies, randomized trials, and Mendelian
randomization studies have all shown that raised LDL-C is a cause of ASCVD.
Throughout the range of LDL-C levels, ‘lower is better’ with no lower
threshold, at least down to ∼1 mmol/L. Lowering LDL-C may yield worthwhile
benefits in patients with average or below average LDL-C who are already
receiving LDL-C-lowering treatment. The proportional reduction in ASCVD
risk achieved by lowering LDL-C (e.g. with a statin, ezetimibe, or
PCSK9-inhibitor) depends on the absolute reduction in LDL-C, with each 1
mmol/L reduction corresponding to a reduction of about one-fifth in ASCVD.

2. PCSK-9 inhibitors. Large trials have shown that PCSK9 inhibitors further
reduce ASCVD risk when given on top of statin-based therapy and their use
may need to be restricted to those at the highest risk for ASCVD.

3. Use of cardiac imaging for risk stratification. CAC score assessment with
CT may be helpful in reaching decisions about treatment in people who are
at moderate risk of ASCVD. Obtaining such a score may assist in discussions
about treatment strategies in patients where the LDL-C goal is not achieved
with lifestyle intervention alone and there is a question of whether to
institute LDL-C-lowering treatment. Assessment of arterial (carotid or
femoral) plaque burden on ultrasonography may also be informative in these
circumstances.

4. Use of ApoB in risk stratification. ApoB may be a better measure of an
individual’s exposure to pro atherogenic lipoproteins, and hence its use
may be particularly helpful for risk assessment in people where measurement
of LDL-C underestimates this burden, such as those with high TG, DM,
obesity, or very low LDL-C.

5. Use of Lp(a) in risk stratification. A one-off measurement of Lp(a) may
help to identify people with very high inherited Lp(a) levels who may have
a substantial lifetime risk of ASCVD. A high Lp(a) plasma level may also be
helpful in further risk stratification of patients at high risk of ASCVD,
in patients with a family history of premature CVD, and to determine
treatment strategies in people whose estimated risk is on the border of
risk categories.

6. Intensification of treatment goals. It is important to ensure that
treatment of the highest-risk patients achieves the largest LDL-C reduction
possible. These Guidelines aim to support this by setting both a minimum
percentage LDL-C reduction (50%) and an absolute LDL-C treatment goal of
<1.4 mmol/L (<55 mg/dL) for very-high-risk patients, and <1.8 mmol/L (<70
mg/dL) for high-risk patients. It is recommended that FH patients with
ASCVD or who have another major risk factor are treated as very-high-risk,
and those with no prior ASCVD or other risk factors as high-risk.

7. Treatment of patients with recent ACS. New randomized trials support a
strategy of intensification of LDL-C-lowering therapy in very-high-risk
patients with ACS (MI or unstable angina). If the specified LDL-C treatment
goal is not achieved after 4–6 weeks with the highest tolerated statin dose
and ezetimibe, it is appropriate to add a PCSK9 inhibitor.

8. Safety of low LDL cholesterol concentrations. To date there are no known
adverse effects of very low LDL-C concentrations [e.g. <1 mmol/L (40
mg/dL)].

9. Management of statin ‘intolerance’. While statins rarely cause serious
muscle damage (myopathy, or rhabdomyolysis in the most severe cases), there
is much public concern that statins may commonly cause less serious muscle
symptoms. Such statin ‘intolerance’ is frequently encountered by
practitioners and may be difficult to manage. However, placebo-controlled
randomized trials have shown very clearly that true statin intolerance is
rare, and that it is generally possible to institute some form of statin
therapy (e.g. by changing the statin or reducing the dose) in the
overwhelming majority of patients at risk of ASCVD.

10. Statin treatment for older people. A meta-analysis of randomized trials has
shown that the effects of statin therapy are determined by the absolute
reduction in LDL-C as well as the baseline ASCVD risk, and are independent
of all known risk factors, including age. Statin therapy in older people
should therefore be considered according to the estimated level of risk and
baseline LDL-C, albeit with due regard to an individual’s underlying health
status and the risk of drug interactions. There is less certainty about the
effects of statins in individuals aged >75 years, particularly in primary
prevention. Statin therapy should be started at a low dose if there is
significant renal impairment and/or the potential for drug interactions,
and then titrated upwards to achieve LDL-C treatment goals.

15 GAPS IN THE EVIDENCE

* Prospective studies are needed to investigate the incremental value of
reclassifying total CV risk and defining eligibility for lipid-lowering
therapy based on CAC scores in individuals at moderate or high-risk.

* Outcome-based comparisons of CAC scores vs. assessment of arterial (carotid
or femoral) plaque burden by ultrasonography for CV risk reclassification in
people at moderate or high-risk are needed.

* Although calibrated country-specific versions of the SCORE system are
available for many European countries, risk charts based on country-specific
cohort data are missing for most countries. Regional total event charts (vs.
mortality-only charts) are needed.

* Total CV risk estimation by means of the SCORE system and, accordingly,
recommendations on eligibility for statins as well as treatment goals are
based on TC, whereas LDL-C is the primary lipid analysis method for
screening, diagnosis, and management.

* There are no outcome-based comparisons of LDL-C vs. ApoB as primary
measurement methods for screening, diagnosis, and management.

* Against a background of genetic and randomized clinical trial evidence
showing no significant effect of increasing HDL levels on the risk of CVD
events, the clinical impact of therapies altering the function of HDL
particles is unknown. More evidence is needed regarding the apparently
adverse association of extremely high levels of HDL-C with clinical outcomes.

* Dedicated studies assessing outcomes with specific Lp(a)-lowering therapies
are warranted.

* More evidence is needed for PCSK9 inhibitors in specific populations,
including patients with severe CKD and on dialysis, patients with HIV
infection, in children and adolescents with FH, after heart transplantation,
and during pregnancy.

* The effects of PCSK9 inhibition on specific body compartments (as with siRNA
or antisense) or only within plasma (as with monoclonal antibodies) remain to
be established.

* How early should a PCSK9 inhibitor be initiated in patients with ACS or
stroke? In view of evidence of sustained clinical benefit associated with the
early initiation of statin treatment in the acute phase of ACS or stroke, the
optimal timing of PCSK9 inhibitor treatment in ACS and stroke patients
remains to be addressed in outcome studies.

* Whether very low LDL-C levels achieved with the combination of statin,
ezetimibe, and PCSK9 inhibitor reduce the need for further PCI remains to be
addressed in outcome studies.

* In patients with chronic HF, a small benefit of n-3 PUFAs has been shown in
one RCT and merits further investigation.

* What is the optimal screening programme for detecting FH?

* In view of limited access to genetic testing in several environments, more
evidence is needed regarding outcomes with only clinical vs. genetic
screening and diagnosis of FH.

* More RCT evidence is required to support the use of statin-based treatment in
older people (aged ≥75 years, but particularly in those aged ≥80 years).

* More RCT evidence is needed for statin treatment in kidney transplant
recipients.

* There are no data on the effects of statins, ezetimibe, or fibrates on CV
events in dyslipidaemic HIV-infected patients.

* More evidence is needed regarding attainment of recommended LDL goals among
very high-risk patients in real-world practice in the era of increasingly
prescribed combination therapies for LDL lowering.