Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis – 2025Table of Contents
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Preamble 13
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1. Introduction 15
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1.1. The Brazilian Population Perspective 15
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1.2. Expanded Focus: From Dyslipidemia to Prevention of Atherosclerosis 15
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1.2.1. Early Phase – Childhood and Adolescence 15
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1.2.2. Intermediate Phase – Young to Middle-Aged Adults 15
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1.2.3. Late Phase – Older Adults and Patients with Established Clinical Disease 15
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1.3. A Stratified Model for Prevention of Atherosclerotic Cardiovascular Disease 15
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1.4. Key Points of the 2025 Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis 15
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1.5. Strength of Recommendation and Certainty of Evidence 16
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1.6. Summary of Recommendations 17
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2. Epidemiology 27
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2.1. Average Plasma Lipid Levels and Prevalence of Dyslipidemia 27
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2.2. Cardiovascular Mortality Attributable to Increased Low-density Lipoprotein Cholesterol 29
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2.3. Data on Treatment and Target Achievement 29
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3. Diagnosis 31
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3.1. Laboratory Assessment of Lipid Parameters and Apolipoproteins 31
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3.1.1. Pre-Analytical and Analytical Phases 31
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3.1.1.1. Pre-Analytical Phase 31
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3.1.1.2. Analytical Phase 32
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3.1.1.2.1. Research-Restricted Methods 32
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3.1.1.2.2. Conventional Methods – Routine Laboratory Practice 32
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3.1.1.2.2.1. Colorimetric Enzymatic Methods 32
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3.1.1.2.2.2. Point of Care Testing 32
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3.1.1.2.2.3. Calculation of Low-Density Lipoprotein Cholesterol 33
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3.1.1.2.2.4. Measurement of Non-High-Density Lipoprotein Cholesterol 33
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3.1.1.2.2.5. Measurement of Apolipoprotein B 33
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3.1.1.2.2.6. Lipoprotein(a) 34
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3.1.1.2.2.7. Reference Values for the Lipid Profile 35
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3.2. Genetic Diagnosis of Dyslipidemias 35
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3.2.1. Genetically-Based Hypercholesterolemias 35
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3.2.1.1. Considerations for Requesting Genetic Testing 35
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3.3. Diagnosis of Hypertriglyceridemia 38
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3.3.1. Familial Chylomicronemia Syndrome 38
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3.3.1.1. Definition 38
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3.3.1.2. Clinical and Laboratory Diagnosis of Familial Chylomicronemia Syndrome 38
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3.3.1.3. Diagnostic Scores 38
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3.3.1.4. Differential Diagnosis 38
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3.3.1.5. Genetic Diagnosis 38
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3.3.1.6. Lipoprotein Lipase Activity 39
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3.3.1.7. Other Diagnostic Tests 39
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4. Risk Stratification 39
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4.1. Cardiovascular Risk Stratification 39
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4.2. Cardiovascular Risk Scores 41
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4.3. Cardiovascular Risk Enhancers 41
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4.3.1. Family History of Premature Cardiovascular Disease 42
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4.3.2. Adiposity and its Manifestations 42
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4.3.3. Chronic Inflammatory Conditions 43
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4.3.4. Organ Transplantation 43
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4.3.5. Women-Specific Cardiovascular Risk-Enhancing Factors 43
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4.3.5.1. Age at Menarche 43
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4.3.5.2. Pregnancy-Related Disorders and Preterm Birth 43
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4.3.5.3. Recurrent Miscarriages 43
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4.3.5.4. Premature Menopause 44
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4.4. Additional Tests 44
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4.4.1. Lipoprotein(a) 44
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4.4.2. High-Sensitivity C-Reactive Protein 44
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4.4.3. High-Sensitivity Cardiac Troponins 44
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4.4.4. B-Type Natriuretic Peptide and N-Terminal Pro-B-Type Natriuretic Peptide 44
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4.5. Markers of Subclinical Atherosclerotic Disease 45
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4.5.1. Coronary Artery Calcium Score 45
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4.5.2. Carotid Artery Ultrasound 45
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4.6. Cardiovascular Risk Stratification in Diabetes 47
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4.7. Categories of Atherosclerotic Cardiovascular Risk 47
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4.8. Particularities of Cardiovascular Risk Stratification in Older Adults 48
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4.9. Particularities of Cardiovascular Risk Stratification in Young Adults 48
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4.10. Cardiovascular Risk Stratification in Childhood and Adolescence 49
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5. Treatment Targets 50
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5.1. Primary and Co-Primary Target: Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol 50
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5.2. Recommendations for Targets According to Cardiovascular Risk Stratification 50
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5.2.1 Individuals at Intermediate Risk 50
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5.2.2. Individuals at Intermediate Risk 51
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5.2.3. Individuals at High Risk 51
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5.2.4. Individuals at Very High Risk 51
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5.2.5. Individuals at Extreme Risk 52
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5.3. Apolipoprotein B 52
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5.4. High-Density Lipoprotein Cholesterol 52
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5.5. Triglycerides 52
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5.6. Lipoprotein(a) 53
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6. Nonpharmacological Treatment 53
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6.1. Lifestyle Recommendations to Improve Lipid Profile 53
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6.1.1. Nutritional Aspects 53
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6.1.2. Carbohydrates 53
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6.1.3. Fats 54
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6.1.4. Soluble Fiber 54
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6.2. Smoking Cessation 54
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6.3. Management of Weight 54
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6.4. Spirituality 55
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6.5. Physical Activity 55
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6.6. Alcohol Intake 55
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6.7. Dietary Supplements and Functional Foods in Dyslipidemia 56
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7. Pharmacological Treatment 56
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7.1. Statins 56
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7.2. Ezetimibe 58
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7.3. Novel Messenger RNA-Targeting Therapies 58
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7.4. Anti-Proprotein Convertase Subtilisin/Kexin Type 9 Therapy 58
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7.5. Bempedoic Acid 59
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7.6. Cholesteryl Ester Transfer Protein Inhibitors and High-Density Lipoprotein Cholesterol–Raising Therapies 59
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7.7. Fibrates 59
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7.8. Omega-3 Fatty Acids 60
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7.9. Apolipoprotein C-III Inhibitors 60
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7.10. Angiopoietin-Like Protein 3 Inhibitors 60
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7.11. Lipoprotein(a) Inhibitors 61
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7.12. Clustered Regularly Interspaced Short Palindromic Repeats and Gene Therapies 61
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7.13. Combination Therapy 62
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7.13.1. Benefits of Combination Therapy 62
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7.13.2. Statin and Ezetimibe Combination 62
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7.13.3 Statin and Proprotein Convertase Subtilisin/Kexin Type 9-Targeted Therapy Combination 62
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7.13.4. Ezetimibe and Bempedoic Acid Combination 62
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7.13.5. Statin, Ezetimibe, and Proprotein Convertase Subtilisin/Kexin Type 9-Targeted Therapy Combination 63
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7.13.6. Statin, Ezetimibe, and Bempedoic Acid Combination 63
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8. Management of Statin Intolerance 64
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8.1. Definition 64
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8.2. Prevalence 64
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8.3. Diagnosis 64
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8.4. Nocebo Effect 64
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8.5. Muscle Symptoms 64
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8.5.1. Clinical Characteristics, Classification, and Management of Statin-Associated Muscle Symptoms 64
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8.5.2. Tolerable and Intolerable Muscle Symptoms 65
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8.5.3. Creatine Kinase Elevation 65
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8.5.4. Rhabdomyolysis 66
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8.5.5. Statin-Induced Immune-Mediated Necrotizing Myopathy 67
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8.6. Factors Associated with Statin Intolerance 67
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8.7. Management of Statin-Intolerant Patients 67
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8.7.1. Discontinuation and Reintroduction of Statin Therapy 67
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8.7.2. Use of Products Without Proven Benefit 68
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8.7.3. Drug interactions of statins 68
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8.7.3.1. Anticoagulants 68
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8.7.3.2. Azole Antifungals 72
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8.7.3.3. Antiretroviral Agents 72
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8.7.3.4. Calcium Channel Blockers 72
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8.7.3.5. Antiarrhythmic Agents 72
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8.7.3.6. Immunosuppressants 72
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8.7.3.7. Macrolides 72
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8.7.3.8 Interactions Between Lipid-Lowering Agents 72
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9. Dyslipidemia in Specific Populations: Clinical Management Considerations 73
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9.1. Heart Failure 73
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9.2. People Living with HIV 74
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9.3. Diabetes 74
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9.3.1. Specific Characteristics of Dyslipidemia in Insulin Resistance and Type 2 Diabetes 75
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9.3.2. Treatment of Dyslipidemia in Patients with Diabetes 75
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9.3.3. Pharmacological Treatment 75
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9.4. Hypothyroidism 76
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9.5. Chronic Kidney Disease 77
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9.6. Obesity 78
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9.7. Older Individuals 79
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9.8. Nonpharmacological Treatment 79
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9.9. Pharmacological Treatment 79
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9.10. Children 80
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9.10.1. Lipid Profile in Childhood 80
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9.10.2. Screening 80
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9.10.3. Primary Dyslipidemias 80
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9.10.4. Homozygous Familial Hypercholesterolemia 80
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9.10.5. Hypertriglyceridemias 80
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9.10.6. Monogenic Hypertriglyceridemia (Severe Hypertriglyceridemias) 80
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9.10.7. Secondary Dyslipidemias 80
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9.10.8. Statin Therapy is Indicated Based on risk in Secondary Dyslipidemias, Particularly in High-Risk Conditions or in the Presence of Risk Factors (Threshold Values for Initiating Treatment) 81
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9.11. Transplant Recipients 81
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9.12. Chronic Liver Diseases 81
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9.12.1. Metabolic Dysfunction-Associated Steatotic Liver Disease 83
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9.12.1.1. Definition 83
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9.12.1.2. Prevalence and Cardiovascular Risk 83
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9.12.1.3. Reducing Cardiovascular Risk 83
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9.12.1.4. Liver Outcomes 83
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9.12.1.5. Safety 83
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9.12.1.6. Intrahepatic Cholestasis 83
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9.12.1.7. Hepatic Cirrhosis 83
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9.12.1.8. Hepatocellular Carcinoma 84
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9.13. Acute Coronary Syndrome 84
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9.14. Immune-Mediated Diseases 85
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9.15. Pregnancy 86
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9.15.1. Gestational Dyslipidemia in Normolipidemic Women 86
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9.15.2. Gestational Dyslipidemia in Women with Pre-Existing Dyslipidemia 86
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9.15.3. Lipoprotein(a) 86
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9.15.4. Pharmacological Treatment 86
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9.15.4.1. Statins 86
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9.15.4.2. New Evidence 86
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9.15.4.3. Bile Acid Sequestrants 87
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9.15.4.4. Lipoprotein Apheresis 87
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9.15.4.5. Ezetimibe 87
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9.15.4.6. Omega-3 Fatty Acids 87
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9.16. Women 87
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10. Conclusion 88
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References 89
Preamble
Despite major advances in understanding the pathophysiology of atherosclerosis and its consequences, as well as the development of new preventive therapies, ASCVD remains the leading cause of death worldwide.1,2 The global rise in obesity and diabetes often leads to dyslipidemia, which is characterized by low levels of high-density lipoprotein cholesterol, high levels of non-high-density lipoprotein cholesterol, and high triglyceride levels.3,4 Of particular concern is the increasing prevalence of ASCVD in low- and middle-income countries, where most of the global population resides. This disease tends to manifest in these populations about a decade or earlier than in high-income countries.5
The importance of clinical guidelines in helping health professionals deliver more effective management and improved outcomes in various clinical situations has been well-documented. Adherence to guidelines improves patient prognosis. Furthermore, guidelines provide a framework that informs the development of public health policies based on solid scientific evidence. They also identify barriers to implementing best practices and offer potential solutions adapted to different regions. The Brazilian Society of Cardiology's current Guideline on Cholesterol Management and Prevention of Atherosclerosis is a prime example of this. It serves as a valuable tool for clinicians dealing with these conditions and for policymakers responsible for implementing measures to reduce the population's burden of lipid metabolism disorders.
Today, the role of elevated blood cholesterol levels in the global burden of atherosclerotic disease is well established. Lowering low-density lipoprotein cholesterol (LDL-c) has been consistently shown to be beneficial across the continuum of cardiovascular risk, with individuals at higher risk of atherothrombotic events — such as myocardial infarction, stroke, revascularization, or cardiovascular death — achieving greater absolute risk reductions from LDL-c decrease. The timing and duration of treatment in the course of atherosclerotic disease are critical and should clearly inform health policies and, above all, their implementation. Nevertheless, most patients worldwide do not achieve the recommended LDL-c decrease needed to minimize their individual ASCVD risk. This is largely due to the underuse of high-intensity statins as first-line therapy, insufficient use of combination strategies, and poor adherence to lipid-lowering regimens — all of which contribute to persistently high cumulative cholesterol exposure. Thus, the importance of early combination therapy is increasingly recognized to achieve better outcomes and have a more significant impact on reducing the atherosclerotic burden.6
It is also well established that LDL-c reduction benefits not only individuals with high cholesterol levels but also those at higher risk for the main clinical manifestations of atherosclerosis.7 Therefore, LDL-c decrease should be considered for all high-risk individuals,8 including those with i) established or previous ASCVD; ii) high-risk conditions such as diabetes, chronic kidney disease, tobacco use, or hypertension, which increase ASCVD risk even in the absence of concurrent lipid abnormalities; iii) extreme elevations of LDL-c with a genetic basis, such as heterozygous familial hypercholesterolemia (FH); iv) high overall cardiovascular risk due to the combined effects of multiple risk factors; v) isolated elevations of atherogenic lipoproteins, including triglyceride-rich lipoproteins (commonly referred to as atherogenic dyslipidemia) or elevated lipoprotein(a) (Lp(a)); and vi) high subclinical coronary atherosclerotic burden.9
The treatment and control of dyslipidemias remain one of the major medical challenges of our time. The availability of up-to-date, well-designed guidelines, such as the current document, provides an essential tool to help achieve the goal of reducing the burden of cardiovascular diseases — and particularly ASCVD.
Fausto J Pinto
1. Introduction
ASCVD remains the leading cause of death worldwide, despite significant advances in the understanding of its pathophysiology and the development of preventive therapies.10 In Brazil, the same pattern holds: ASCVD is the condition with the greatest impact on morbidity and mortality, affecting millions of people and placing a heavy burden on the health care system.11
Particularly concerning is the rising prevalence of ASCVD in low- and middle-income countries, such as Brazil, where most of the global population lives.3 In such settings, ASCVD often manifests at least a decade earlier than in high-income countries, affecting not only individual health but also economic productivity during the most active years of life. The burden further extends to family members and caregivers, compounding the social impact of ASCVD.
Atherosclerosis is a chronic, silent, progressive disease that begins in childhood. Histopathological studies have shown that early changes in the arterial wall, such as fatty streaks, may appear as early as the first decade of life. Therefore, ASCVD should not be viewed solely as a disease of adulthood or old age, but rather as a continuous process with multiple opportunities for intervention and prevention throughout life.12,13
Thus, updated guidelines tailored to the Brazilian context are essential for developing strategies to prevent, diagnose early, and effectively treat ASCVD at all stages of life (Central Illustration).
1.1. The Brazilian Population Perspective
With an estimated population of 218,56 million in 2025, Brazil has an age distribution that poses specific challenges for CVD prevention. Estimates indicate that:
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Around 25% of the population (about 54 million) are under the age of 20;
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Around 54% (about 118 million) are between 20 and 60 years old;
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And 21% (about 45 million) are over the age of 60.
This distribution underscores the need for preventive strategies tailored to each stage of life and to the degree of atherosclerosis progression, with an emphasis on early, continuous, targeted interventions.
1.2. Expanded Focus: From Dyslipidemia to Prevention of Atherosclerosis
Although dyslipidemia is a central factor in the development of atherosclerosis, the current guideline adopts a broader approach, with the primary goal of preventing ASCVD. According to data from the GBD (Global Burden of Disease) study, increased LDL-c and hypertension are the two main risk factors responsible for the highest number of CV deaths in Brazil.14 Thus, the guideline proposes a life-course model of action with specific and graduated interventions:
1.2.1. Early Phase – Childhood and Adolescence
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Primordial prevention focused on promoting healthy habits and preventing the onset of risk factors.
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Screening for genetic dyslipidemias, such as FH, with early intervention in children and adolescents.
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No clinical manifestations, but the possibility of initial histopathological changes in the arterial wall.
1.2.2. Intermediate Phase – Young to Middle-Aged Adults
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Frequent presence of subclinical atherosclerotic disease (SAD) detectable by imaging methods (eg, carotid ultrasound, coronary artery calcium [CAC] score).
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Indication for early and intensive intervention through lifestyle modification and, when necessary, pharmacologic therapy.
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Objective: to halt disease progression and reduce the lifetime risk of major CV events.
1.2.3. Late Phase – Older Adults and Patients with Established Clinical Disease
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Presence of manifest ASCVD, such as acute myocardial infarction (MI), stroke, or peripheral arterial disease (PAD).
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Need for intensive treatment and aggressive therapeutic targets, especially for lipid control.
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Emphasis on individuals at higher cardiovascular risk within the continuum and on reducing the recurrence of cardiovascular events.
1.3. A Stratified Model for Prevention of Atherosclerotic Cardiovascular Disease
Atherosclerosis must be understood as a chronic, progressive, and early-onset condition that demands a preventive approach across the entire life course. The current guideline proposes a model of care that goes beyond isolated dyslipidemia control, incorporating individualized risk stratification, the use of emerging biomarkers (eg, Lp(a), apolipoprotein B [ApoB], and high-sensitivity C-reactive protein [hs-CRP]), as well as imaging tools for the detection of subclinical atherosclerosis, such as CAC scoring, and the adoption of evidence-based therapeutic targets.
By recognizing the heterogeneity of the Brazilian population and the complexity of ASCVD, the current guideline reinforces the importance of integrated public policies, health education, and equitable access to effective diagnostic and therapeutic strategies.
1.4. Key Points of the 2025 Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis
The 2025 Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis updates and expands upon the concepts of the 2017 version, maintaining a focus on risk stratification while adopting a more refined and personalized approach. The focus is centered on the continuum of cardiovascular risk, beginning with the early and accurate identification of aggravating factors — such as a family history of premature cardiovascular disease and obesity, among others — and progressing toward stratification into very high and extreme risk categories, where therapeutic approaches should be more intensive. This assessment includes not only classical risk factors but also biomarkers, such as Lp(a), ApoB, and hs-CRP, as well as imaging tools for the detection of subclinical atherosclerosis, such as CAC scoring (Box 1.1).
Top 10 Key Messages from the 2025 Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis
Based on this expanded stratification, therapeutic targets are more intensive: LDL-c levels < 50 mg/dL for very high-risk patients and < 40 mg/dL for those at extreme risk. Combination therapy is now recommended as first-line treatment in these groups, including statins combined with ezetimibe, anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) therapy, and bempedoic acid (BA) — particularly in cases of statin intolerance or the need for further cardiovascular (CV) risk reduction.
Another important advancement is the structured management of statin intolerance, which is often underestimated in clinical practice. The guideline offers clear algorithms for diagnosis and effective therapeutic alternatives.
Finally, recognizing the specific challenges faced in Brazil — such as low treatment adherence and difficulty achieving therapeutic targets — the current guideline aims not only to update technical knowledge but also to transform clinical practice, promoting better outcomes and reducing the burden of CVD in the country.
1.5. Strength of Recommendation and Certainty of Evidence
The recommendations were developed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, which classifies the strength of recommendation (strong or weak/conditional) and the certainty of evidence (high, moderate, low, or very low) (Boxes 1.2 and 1.3).
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The development of this guideline was structured into thematic chapters, each coordinated by experts with recognized expertise in their respective fields. Each coordinator was responsible for assembling a group of authors, with whom a critical review of the available scientific literature was carried out, aiming to base the recommendations on the best available evidence.
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The working groups held periodic meetings to discuss the topics and draft the recommendations, under the supervision of the guideline's general coordination. The recommendations were subsequently reviewed and refined by the editorial committee, based on predefined technical and scientific criteria.
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The final text of each chapter was submitted for review and approval by all committee members, ensuring methodological alignment and consistency across the content presented.
1.6. Summary of Recommendations
Recommendations for the collection and interpretation of the lipid profile in the diagnosis of dyslipidemia
Recommendations for genetic testing for familial hypercholesterolemia in different clinical scenarios
Recommendations on dietary supplements, functional foods, and lifestyle measures in the management of dyslipidemias
Recommendations for laboratory diagnosis and treatment of dyslipidemia in patients with acute coronary syndrome
2. Epidemiology
2.1. Average Plasma Lipid Levels and Prevalence of Dyslipidemia
Epidemiological data on dyslipidemias in Brazil can be drawn from population-based surveys and observational studies. In the 2014-2015 Brazilian National Health Survey (PNS), blood samples were collected from a subpopulation of 8,534 adults to estimate representative lipid profile values for the Brazilian population. The mean total cholesterol and LDL-c levels were 185 mg/dL and 105 mg/dL, respectively, with slightly higher values observed in women compared to men (Figure 2.1). One in three individuals had total cholesterol > 200 mg/dL and one in five had LDL-c > 130 mg/dL, with higher prevalence among women (Figure 2.2). Lower levels of total cholesterol and LDL-c were found in individuals aged 18-29, intermediate levels in those aged 30-44, and the highest levels in those aged 45 and older. Increased total cholesterol and LDL-c were more prevalent among individuals with lower educational attainment.11,15
Blood lipid levels in the Brazilian population stratified by sex. Mean levels of TC, LDL-c, and HDL-c, and median TG levels from the 2014-2015 PNS and the baseline of the ELSA-Brasil study. Sources: 2014-2015 PNS15 and ELSA-Brasil database. ELSA-Brasil: Brazilian Longitudinal Study of Adult Health; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; PNS: National Health Survey; TC: total cholesterol; TG: triglycerides.
Lipid abnormalities in the Brazilian population stratified by sex. Prevalence of lipid abnormalities according to the 2014-2015 PNS, the 2019 PNS, the 2016 Vigitel, and the baseline of the ELSA-Brasil study. ELSA-Brasil: Brazilian Longitudinal Study of Adult Health; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; PNS: National Health Survey; TC: total cholesterol; TG: triglycerides; Vigitel: Brazilian Telephone Survey for Surveillance of Risk and Protection Factors for Chronic Diseases. Sources: 2014-2015 PNS,15 2019 PNS,16 2016 Vigitel,17 and ELSA-Brasil database.
Compared to the 2014-2015 PNS, lower rates of self-reported dyslipidemia were observed in the 2019 PNS16 (a nationally representative study involving 88,531 adults) and in the 2016 Brazilian Telephone Survey for Surveillance of Risk and Protection Factors for Chronic Diseases17 (Vigitel) — based on 53,210 adult interviews in the capital cities of Brazil's 26 states and the Federal District (Figure 2.2).
Another source of lipid data in the Brazilian population is the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a prospective cohort of 15,105 public servants initially aged 35 to 74 years (mean age 52 ± 9 years) from six capital cities (Salvador, Belo Horizonte, Vitória, Rio de Janeiro, São Paulo, and Porto Alegre).18 Compared to the 2014-2015 PNS, the ELSA-Brasil baseline (2008-2010) revealed higher levels of total cholesterol, LDL-c, and high-density lipoprotein cholesterol (HDL-c) as well as substantially greater prevalence of increased total cholesterol or LDL-c (Figure 2.1 and Figure 2.2). Differences in population characteristics may account for such discrepancies.
ELSA-Brasil was also used to estimate the prevalence of FH based on the Dutch Lipid Clinic Network criteria, stratified by sex and skin color. The overall prevalence was 3.8 per 1,000 individuals, equivalent to 1 in every 263. This rate was higher in women (1:244) than in men (1:333), and higher among individuals identifying as Pardo (mixed-race) (1:204) and Black (1:156), compared to those identifying as White (1:417).19
Epidemiological information on dyslipidemias in children and adolescents was provided by ERICA (Study of Cardiovascular Risk in Adolescents), a nationwide, school-based survey involving 38,069 adolescents aged 12 to 17 years living in all 27 Brazilian state capital cities or surrounding areas, conducted between 2013 and 2014. The main results are shown in Figure 2.3. One in five adolescents had total cholesterol ≥ 170 mg/dL, with higher prevalence among women than men.20
Blood lipids in children and adolescents in Brazil stratified by sex, according to data from ERICA. A. Mean levels of TC, LDL-c, HDL-c, and TG. B. Prevalence of lipid abnormalities. Source: ERICA study.20 ERICA: Study of Cardiovascular Risk in Adolescents; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides.
2.2. Cardiovascular Mortality Attributable to Increased Low-density Lipoprotein Cholesterol
According to data from the GBD study, increased LDL-c is the second leading risk factor for CV deaths in Brazil, following hypertension. The age-standardized CV mortality rate attributable to increased LDL-c in Brazil decreased from 49.6 to 32.1 per 100,000 inhabitants between 2001 and 2021.1 This reduction reflects advances in risk factor control, improved access to health care services, and better quality of care. However, considering population growth over the same period, the estimated absolute number of CV deaths attributable to increased LDL-c increased from 60,716 to 79,604,1 underscoring the epidemiological relevance of hypercholesterolemia.
2.3. Data on Treatment and Target Achievement
There is a lack of data on lipid-lowering treatment and target attainment in Brazil, which makes it difficult to accurately define the national dyslipidemia treatment landscape. ELSA-Brasil showed that the country was far from the ideal scenario between 2008 and 2010: among participants with increased LDL-c, 42.3% were using lipid-lowering therapy, and only 58.3% achieved the goals recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines.21 The 2006-2007 L-TAP 2 (Lipid Treatment Assessment Project 2) study, which assessed lipid management in nine countries including Brazil (n = 391), found a similar proportion (62.1%) of Brazilians within LDL-c targets.22 A particularly concerning scenario emerges when focusing on individuals with severe dyslipidemia (LDL-c > 190 mg/dL): in a Brazilian private institution study with data from 2004 to 2019, only 5.9% of these patients initially received lipid-lowering medication. This increased to 45.4% by the end of follow-up, but only 19.1% achieved an LDL-c reduction greater than 50%.23
More recent evidence on dyslipidemia management in Brazil was reported by the NEtwork to Control Atherothrombosis (NEAT) registry, which involved 25 centers (56% public) across all five regions of the country. The study assessed 2,003 patients with coronary and/or PAD between 2020 and 2022. About 5.1% were not on statin therapy, and among those who were, 55.4% were not on high-intensity therapy. Among patients with available LDL-c measurements, only 14.4% had LDL-c levels below 50 mg/dL, while approximately 30% had levels ≥ 100 mg/dL (Figure 2.4). The low adoption of combination therapies is also noteworthy: a total of 6.19% of patients were on concomitant high-intensity statin and ezetimibe therapy, and only 1 patient (0.05%) was receiving triple therapy with high-intensity statin, ezetimibe, and a PCSK9 inhibitor, as illustrated in Figure 2.5.24 The main barrier to evidence-based therapy was not the cost, but rather physicians’ decisions not to prescribe these strategies.25
Distribution of LDL-cholesterol (LDL-c) among treated patients according to therapeutic groups in the NEAT Study population with available LDL-c (n = 1035): LDL-cholesterol range n (%). *Patients without treatment (n = 36) and those on anti-PCSK9 therapy (n = 2) were excluded from the analysis.
Distribution of therapeutic groups among patients with available LDL (n = 2003): therapeutic group n (%). *1 patient in the group without statin use and with ezetimibe was receiving anti-PCSK9 therapy.
Alarming results were reported in a real-world cross-sectional study within Brazil's Family Health Strategy program, using data from 2016 to 2021. Among more than 35,000 adults with a history of MI or stroke, only 6.7% and 0.6% were on statins and high-dose statins, respectively.26
Outside Brazil, LDL-c target attainment is also far from optimal. The DA VINCI (EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care) study assessed goal achievement in primary and secondary prevention patients prescribed lipid-lowering therapy (94% on statins). Data were collected from 2017 to 2018 across 18 European countries. Only 33% achieved the targets set by the 2019 European guideline (54% according to the 2016 guideline), in the context of low use of high-intensity statins (22% in primary prevention and 42% in secondary prevention). Additionally, combination therapy rates were very low: 9% with ezetimibe and 1% with a PCSK9 inhibitor.27
In the multicenter Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry in the United States (2016-2020), among secondary prevention patients not using PCSK9 inhibitors, lipid-lowering therapy was intensified in only 22% of those with LDL-c ≥ 100 mg/dL and in 14% of those with LDL-c between 70 and 99 mg/dL over a 2-year period. LDL-c levels < 70 mg/dL were achieved by 21% and 34% of patients in the respective groups. By the end of the study, ezetimibe had been added to only 5.3% of patients.28
The PURE (Prospective Urban Rural Epidemiology) study clearly illustrates the impact of socioeconomic conditions on the use of statins. Among participants in secondary prevention, statins were used by only 3.3% of individuals in low-income countries, 4.3% in lower-middle-income countries, 17.6% in upper-middle-income countries, and 66.5% in high-income countries.29 Another study conducted between 2013 and 2019 with over 116,000 individuals (more than 9,000 with a history of CVD) across 41 low- and middle-income countries showed statin use in only 8% of eligible individuals in primary prevention and 22% in secondary prevention.30
Simvastatin is widely available in Brazil's public Unified Health System (SUS), while atorvastatin is only accessible through costly programs, and ezetimibe is offered at select cardiology centers. PCSK9 inhibitors are accessible only through out-of-pocket payments by patients. Barriers such as these hinder the implementation of combination lipid-lowering therapy and the achievement of LDL-c targets in the general population.31 Furthermore, follow-up testing is often not routinely performed, whether for safety monitoring or lipid profiling.32 This compromises the early identification of rare adverse events and undermines guideline-based recommendations for goal-directed lipid management, ultimately reducing the quality of care.33
Therefore, despite having demonstrated efficacy and safety for over 30 years, including reducing CV mortality in both primary and secondary prevention studies, statins are not being used as much as expected. Furthermore, cholesterol control and achievement of guideline-recommended targets are inadequate across many regions worldwide. Brazil is a country with significant regional income disparities. Increasing the use of statins among eligible individuals and consequently raising the proportion of people who reach lipid targets poses a major public health challenge there. Nevertheless, effective action must be taken to address this issue and lessen the societal impact of CVD.
3. Diagnosis
3.1. Laboratory Assessment of Lipid Parameters and Apolipoproteins
3.1.1. Pre-Analytical and Analytical Phases
Lipids circulate in the bloodstream bound to specific proteins, forming complexes known as lipoproteins. The accuracy of lipoprotein measurement depends on two stages of the laboratory process: the pre-analytical phase and the analytical phase. The pre-analytical phase involves collection procedures, patient instructions, sample transport, and preparation. This phase also considers intrinsic patient-related factors, such as lifestyle, use of drugs, and comorbidities. The analytical phase refers to the methods and procedures employed by laboratories.34,35
3.1.1.1. Pre-Analytical Phase
This phase includes all procedures performed before the patient's sample is processed by laboratory equipment.
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Biological variation: Lipoprotein levels can fluctuate over time, known as intra-individual biological variation.36
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Tourniquet use during venipuncture: Hemoconcentration may occur within 1 minute of applying a tourniquet, which can potentially alter the lipid profile. To minimize this effect, release the tourniquet as soon as the needle enters the vein.37
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Patient preparation for sample collection: When preparing for lipid profile testing, it is recommended that patients maintain a stable metabolic state and their usual diet. Deviation from the usual diet (eg, alcohol intake or high-fat meals), as well as strenuous physical activity on the day before the test, may temporarily alter lipid levels. Several guidelines indicate that fasting is not necessary for initial lipid testing. Triglycerides (TG) levels are the most likely to be affected in nonfasting samples. Increased TG, in turn, may reduce the accuracy of LDL-c calculated using the Friedewald formula, but this can be mitigated by using the Martin/Hopkins equation.38
Laboratories should adapt their protocols to allow for flexible fasting durations, while always respecting the referring physician's instructions. Test reports should specify whether the sample was collected in a fasting or 12-hour fasting state, according to the physician's request. In some specific clinical situations (e.g., familial genetic hyperlipidemia), in which the TG concentration is very high (> 440 mg/dL), a repeat lipid profile after a 12-hour fast should be requested. Physicians should interpret lipid profile results in light of the indication for testing, the patient's metabolic state, and overall risk stratification.39
3.1.1.2. Analytical Phase
Several methods are available and routinely used in clinical laboratories. Others are restricted to research and are rarely applied in clinical practice due to low throughput and/or high cost.
3.1.1.2.1. Research-Restricted Methods
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Ultracentrifugation:40 this is the reference method for separating different lipoproteins, based on the particles’ buoyancy properties relative to their equilibrium density under high gravitational force. Ultracentrifugation allows for the separation of most lipoproteins: LDL, intermediate-density lipoprotein (IDL), Lp(a), HDL, very LDL (VLDL), and chylomicrons. Despite its strengths, this method is not suitable for routine laboratory use due to its high cost and time-consuming nature and is thus limited to research protocols.
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Nuclear magnetic resonance (NMR) spectroscopy: the expression "atherogenic particle count by nuclear magnetic resonance spectroscopy" refers to the quantification of potentially atherogenic lipoprotein particles — primarily LDL, but also VLDL, IDL, and Lp(a) using NMR spectroscopy.41-43 This method is recognized and validated in the medical literature for assessment of CV risk, as the concentration of atherogenic particles (especially small, dense LDL) is more strongly associated with CV outcomes than simple LDL-c levels. NMR enables direct quantification of lipoprotein particle numbers in plasma, based on the physical and chemical properties of lipids and apolipoproteins. The most clinically applied version is proton NMR (1H-NMR), which analyzes specific signals from methyl and methylene groups in lipids, allowing for determination of the number and size of lipoprotein subclasses, including LDL, VLDL, and HDL.
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Mass spectrometry (MS): MS is playing an increasingly important role in evaluating dyslipidemia by going beyond the traditional quantification of total cholesterol, LDL, HDL, and TG. MS-based approaches, especially lipidomics techniques, enable the detailed characterization of plasma lipid profiles and lipoprotein subclasses. This offers insights into the molecular structure of lipids and apolipoproteins across different lipoprotein fractions.44-46 In a diagnostic context, MS has been used to identify lipid biomarkers associated with hypercholesterolemia. These biomarkers include specific sphingolipids, such as ceramides, and cholesterol sulfate. They have strong discriminatory power for diagnosis and CV risk stratification.44 Additionally, MS enables the simultaneous analysis of hundreds to thousands of lipid species with high specificity, reproducibility, and robustness, even in large-scale studies. This makes MS particularly relevant for precision medicine and epidemiological research.45 The ability to quantify regulatory proteins, such as PCSK9, at very low levels enhances MS's potential for studying lipid metabolism and the response to targeted therapies.46 In summary, MS — through lipidomic and proteomic approaches — provides an in-depth, precise evaluation of dyslipidemia. This method has the potential to identify new biomarkers, clarify pathogenic mechanisms, and enhance CV risk stratification. Thus, it complements and expands upon conventional laboratory methodologies.44-46 However, several limitations hinder its broader adoption in routine laboratory and clinical settings, including extremely high equipment costs, lack of standardized and validated protocols (often developed in-house), limited availability of trained personnel to operate the technique, and low levels of automation and integration in clinical laboratories.47
3.1.1.2.2. Conventional Methods – Routine Laboratory Practice
3.1.1.2.2.1. Colorimetric Enzymatic Methods
These are currently the most used methods in clinical laboratories for determining TC, HDL-c, and TG. A number of commercial diagnostic kits show good correlation and low coefficient of variation for TC and TG, allowing for inter-laboratory comparison using the same sample. However, for HDL-c, differences of up to 15% may be observed between available methods. These techniques remain the preferred option due to their high sensitivity and specificity, operational simplicity, low cost, and compatibility with automation in clinical laboratories. To measure LDL-c, direct colorimetric methods are available, but they show considerable variability between different diagnostic kits and are not routinely used in clinical practice. Instead, calculation formulas are most commonly employed in both clinical and laboratory settings.
3.1.1.2.2.2. Point of Care Testing
The term point of care testing (POCT) is widely recognized in the global literature and refers to small devices that perform bedside testing. For lipid profile evaluation, these devices use whole blood samples obtained via capillary puncture. Many portable POCT devices are currently available and approved for use in dyslipidemia assessment. Depending on the device, they may assess TC, HDL-c, TG, and even directly measure LDL-c.48,49
The main advantage of this technology is that it allows patients to remain close to the testing site, with immediate results — especially useful in intensive care and primary health care settings. One important consideration is that different methodologies and manufacturers are involved in these small devices. Proper validation of each device is essential before clinical implementation. Validation should involve comparing results with those from a certified clinical laboratory with monitored processes (ie, an accredited laboratory).
After validation for routine use, regular quality control procedures must be implemented to ensure the reliability of test execution. Both validation and quality control are mandated by Brazil's National Health Surveillance Agency under Collegiate Board Resolution No. 978 of June 6, 2025.50 This regulation permits testing using capillary samples in isolated clinics and mobile services (eg, community health campaigns).
Despite technological advances, POCT still shows greater analytical variability when compared to serum-based testing in clinical laboratories. Another point of concern is that the proper execution of POCT requires operator training and a thorough assessment of all procedural steps. Factors that may directly impact result accuracy include ambient temperature, relative humidity, and the volume of whole blood applied to the device.51
When evaluating market options for implementing lipid profiling via POCT, it is advantageous to choose equipment capable of performing a full lipid panel, including HDL-c, to enable the calculation of non-HDL-c. This parameter is essential as it allows for the evaluation of atherogenic lipoproteins and CVD risk.
Although POCT tests still carry a considerable cost, their advantages in lipid profiling are numerous — such as in FH screening, workplace health programs, community outreach in remote areas, and testing in children and older adults with difficult venous access, as well as other high-risk situations.52
3.1.1.2.2.3. Calculation of Low-Density Lipoprotein Cholesterol
The Friedewald formula was widely used for many years to estimate LDL-c values; however, it has known limitations. Martin et al.53 proposed an alternative method for estimating LDL-c using ultracentrifugation as a reference. Through statistical modeling, they defined different divisors for TG to more accurately estimate VLDL cholesterol levels. To obtain these divisors, patient non-HDL-c and TG levels are required. Using this new divisor (x), the formula becomes: LDL-c = TC – HDL-c – TG/x, where x ranges from 3.1 to 11.9.
Several other formulas have been described — and continue to be developed — for estimating LDL-c. In a recent publication, Samuel et al. evaluated 23 formulas cited in literature, and the Martin/Hopkins formula showed superior comparative performance.38
Notably, all formulas lose accuracy when TG levels are high, particularly when > 800 mg/dL.
3.1.1.2.2.4. Measurement of Non-High-Density Lipoprotein Cholesterol
Non-HDL-c represents the cholesterol fraction in plasma lipoproteins other than HDL and is calculated by subtracting HDL-c from TC: non–HDL-c = TC – HDL-c. The purpose of using non-HDL-c is to estimate the amount of atherogenic lipoproteins circulating in the plasma, particularly in individuals with increased TG.54
3.1.1.2.2.5. Measurement of Apolipoprotein B
ApoB is the main structural protein present in atherogenic lipoproteins and acts as a ligand for the LDL receptor. Its measurement provides a direct estimate of the total concentration of circulating atherogenic lipid particles, since there is a single ApoB molecule in each atherogenic lipoprotein: LDL, VLDL, IDL, and Lp(a). In the general population, LDL-c and ApoB levels are highly correlated and generally provide similar information regarding the risk of ASCVD. However, in individuals with diabetes, obesity, or metabolic syndrome (MetS) — conditions often associated with increased TG — the isolated measurement of LDL-c may underestimate the total concentration of ApoB-containing lipoproteins.55 This occurs because, in the presence of high TG levels, part of the cholesterol in LDL particles is replaced by TG, which promotes the formation of small, dense LDL particles. These more atherogenic particles make LDL-c a less reliable reflection of the actual number of LDL particles.
Approximately 20% of these patients present a discordance between measured LDL-c and ApoB levels.56 Therefore, in the presence of increased TG, the estimation of the concentration of atherogenic particles may provide greater accuracy for assessment of CV risk. In such cases, non-HDL-c (indirectly) and ApoB (directly) provide a more precise evaluation. Non-HDL-c therefore represents the TC carried by ApoB-containing lipoproteins, while ApoB directly estimates the number of atherogenic particles in plasma. Comparative studies in population cohorts have shown that both markers are equivalent indicators of CV risk for most individuals. Analyses of CV events in the UK Biobank57 and a meta-analysis of prospective cohort studies in individuals at risk of or with CVD have demonstrated similar risk assessment capabilities with both markers.58 On the other hand, more recent publications suggest that a subgroup of individuals — estimated at 8%-23% — present discordant ApoB and non-HDL-c levels, with ApoB emerging as a better predictor of coronary calcification and CV events.59
ApoB also offers more accurate assessment of atherogenic lipoproteins in the setting of very low LDL-c. Importantly, ApoB levels are not significantly altered in the postprandial state in individuals with TG < 400 mg/dL.60
One limitation of the widespread use of ApoB is the lack of well-established thresholds for initiating or intensifying pharmacological therapy, compared to LDL-c or non-HDL-c levels.
3.1.1.2.2.6. Lipoprotein(a)
Lp(a) is a particle similar to LDL in that ApoB is covalently bound to a molecule called apolipoprotein(a) [apo(a)]. In addition to its pro-atherogenic effects, Lp(a) has pro-inflammatory effects, likely related to its oxidized phospholipid content. Moreover, the structural resemblance of apolipoprotein(a) to plasminogen raises the possibility of pro-thrombotic effects.
Plasma concentrations of Lp(a) are not influenced by diet, age, sex, fasting state, or lifestyle, and are largely (> 90%) genetically determined. Individual values are generally stable throughout life; therefore, repeated measurements are not necessary for assessment of risk. Measuring Lp(a) is challenging due to variations among analytical methods, partly because of the apolipoprotein(a) structure, which can vary widely in size.
Lp(a) concentrations should preferably be measured using a method that minimizes the impact of isoform size. The recommendation is to measure the concentration of circulating particles (in nmol/L). If this is not available, measuring Lp(a) mass concentration (in mg/dL) is acceptable.61 The current guideline does not recommend converting mass units to molar units due to poor accuracy.
An Lp(a) concentration > 50 mg/dL (or > 125 nmol/L) is found in approximately 20% of individuals of European and South Asian descent, 40% of African Americans, and fewer than 10% of East Asians.62 However, larger studies involving different ethnic groups are needed. Lp(a) concentrations are generally 5%-10% higher in women than in men. In men, Lp(a) levels remain relatively constant, while in women, they tend to increase slightly after menopause.63
Population studies have shown a linear relationship between higher Lp(a) levels and increased risk of MI and aortic valve calcification. Increased Lp(a) levels also increase the risk of recurrent ASCVD in a dose-dependent manner. Importantly, high Lp(a) is a risk factor even in individuals with low LDL-c levels.64
Individuals with extremely high Lp(a) levels (≥ 180 mg/dL or 390 nmol/L) are at significantly increased CV risk, with event rates comparable to other genetic dyslipidemias for which family screening is recommended.65
Mendelian randomization studies have clearly shown that genetic variants in the LPA locus, which exclusively regulate Lp(a) levels, are strongly associated with coronary artery disease (CAD) risk, suggesting a causal relationship between Lp(a) and ASCVD. Genetic studies also suggest that major reductions in Lp(a) levels (> 60%) may be necessary to reduce CV events.66 Newer investigational agents — such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which can reduce serum levels by up to 99% — are currently being evaluated in clinical trials.67
Notably, commonly used lipid-lowering medications, such as statins and ezetimibe, do not reduce Lp(a) levels. Currently available therapies that moderately reduce Lp(a) (by 20%-30%) include PCSK9 inhibitors. Preliminary evidence suggests that treatment with PCSK9 inhibitors after acute coronary syndrome (ACS) in patients with very high Lp(a) may reduce CV events, independent of LDL-c decrease; however, these findings are not yet sufficient to support routine use in individuals with increased Lp(a).
Apheresis is not commonly used in our setting, as it is expensive, invasive, and time-consuming for both patients and medical teams.
In summary, Lp(a) is a prevalent risk marker for ASCVD that is still not routinely assessed. Its association with both incident and recurrent CV events, along with its potential to improve CV risk stratification, supports universal screening to identify individuals with very high levels. Although current data support the potential role of Lp(a) as a therapeutic target in the future, we still lack randomized clinical trial (RCT) results for therapies that specifically lower Lp(a).
In this context, for primary prevention, we recommend that patients with Lp(a) ≥ 50 mg/dL (or ≥ 125 nmol/L) receive early, intensive counseling on lifestyle modification and management of other risk factors. Vascular imaging studies may also be considered to detect early SAD in selected individuals, as well as to support earlier initiation of statins or other lipid-lowering therapies — especially in individuals at intermediate risk and/or those at low risk with moderately increased LDL-c levels.
In secondary prevention, the presence of increased Lp(a) is strongly predictive of recurrent events and suggests the need for more intensive LDL-c-lowering therapy and stricter control of other risk factors. Given the elevated Lp(a) levels in the index patient — whose concentration is largely genetically determined — we recommend conducting cascade screening of family members to identify other potential carriers and to assess the associated cardiovascular risk.
3.1.1.2.2.7. Reference Values for the Lipid Profile
This update suggests that the reference and therapeutic target values for the lipid profile (in adults over 20 years old) should be presented according to the metabolic state preceding sample collection — either fasting or 12-hour fasting. Thus, the reference and target values, determined based on the assessment of CV risk estimated by the requesting physician, are presented in Table 3.1 and should be included in laboratory reports nationwide to ensure consistency in the treatment of dyslipidemias. As with LDL-c and non-HDL-c, the reference values vary according to the estimated CV risk. In this update, therapeutic target values for these variables are suggested according to risk category. The parameters TC, HDL-c, LDL-c, and non-HDL-c are not influenced by food intake. For TG in the nonfasting state, the desirable value is < 175 mg/dL. The laboratory should state the fasting time in the report as either "nonfasting" or "12-hour fasting," according to the physician's criteria. The report should also include reference values for TG in both fasting and nonfasting states.
Reference values or therapeutic targets for the lipid profile, apolipoprotein B, and lipoprotein(a)
3.2. Genetic Diagnosis of Dyslipidemias
3.2.1. Genetically-Based Hypercholesterolemias
3.2.1.1. Considerations for Requesting Genetic Testing
Genetic testing allows identification of the type and severity of the variant (defective LDLR gene vs. null LDLR gene), which correlates with the degree of hypercholesterolemia and the risk of developing CAD, including premature CAD; carriers of null variants in the LDLR gene have a more severe phenotype,68,69 while non-null variants in LDLR gene as well as pathogenic variants in the APOB and PCSK9 genes, generally present with a milder phenotype.69 The definitions genotype-positive and phenotype-positive for FH should be used to identify and treat the entire spectrum of patients with FH who have a detected pathogenic variant [genotype-positive], those without [phenotype-positive, genotype-negative], and those who have not undergone genetic testing.
Genetic confirmation positively influences the initiation of lipid-lowering therapy, adherence, and LDL-c decrease;70-72 it also facilitates cascade screening of family members for FH. Since it is an autosomal semi-dominant genetic condition, screening relatives of an affected individual (index case or proband) "at risk" can be highly effective in identifying additional individuals with FH who will require treatment.71,73 It helps identify new patients with FH74-77 and contributes to the prevention of CAD, MI, and death.78-80 Genetic cascade screening can lower the age at which affected relatives are diagnosed compared to index cases81 and decrease TC and LDL-c levels in those relatives.71 Guidelines on FH recommend that when a pathogenic variant is found in an index case, that specific variant should be used to screen affected family members, reducing screening costs.82,83
Genetic testing plays an important role in pre- and post-test genetic counseling. Testing the proband provides accurate risk information during counseling and guides the proper approach for family genetic cascade screening. It also enables molecular-level discrimination between individuals with monoallelic semi-dominant hypercholesterolemia, biallelic monogenic semi-dominant (formerly simple homozygous), biallelic monogenic semi-dominant with two distinct variants (formerly compound heterozygous), biallelic digenic semi-dominant (formerly double heterozygous), and biallelic recessive with two identical copies or one copy each of two distinct variants (formerly autosomal recessive).84
Specifically for those with biallelic digenic variants, the proband's parents should be tested for the identified variants to determine which variant was inherited from the mother and which from the father, and/or to determine if one of the variants is a de novo mutation — which, although rare, can occur. All maternal and paternal relatives with FH should be tested to detect the variant on each side of the family. Without this type of screening, probands with FH carrying two distinct variants may be misclassified as severe heterozygotes, which could negatively impact family members at risk who remain unaware that both sides of the family are affected due to the presence of two pathogenic variants in the proband.85
The American Society of Human Genetics recommends genetic testing in children and adolescents when clinical intervention is warranted.86 In heterozygous FH (HeFH), statin therapy should be started between ages 8 and 10, and lifestyle interventions should begin even earlier. In children with biallelic FH, high-intensity treatment should be initiated at diagnosis.87 If untreated, children with FH are at increased risk of coronary events in adulthood due to cumulative exposure to increased LDL-c levels, with many experiencing CV events at a young age. Children with FH who begin statin therapy early have lower event rates than their parents.88
We recommend that the genetic panel for FH include the following genes: LDLR, APOB, PCSK9, and LDLRAP1. The latter gene is responsible for the autosomal recessive form of FH and includes biallelic variants. Additionally, the panel should include the ABCG5/ABCG8 genes, which cause sitosterolemia, and the LIPA gene, which causes lysosomal acid lipase deficiency (LAL-D) — both of which are phenocopies of FH84 and require different therapeutic approaches. Genetic testing also allows inference of polygenic forms when no pathogenic variant is found (genotype-negative) in an individual with a phenotype-positive presentation.84 In such cases, cascade genetic screening is not considered cost-effective.
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3.3. Diagnosis of Hypertriglyceridemia
3.3.1. Familial Chylomicronemia Syndrome
3.3.1.1. Definition
Fasting plasma TG levels are normally < 150 mg/dL, and in the postprandial state, values < 175 mg/dL are considered normal.37 TG levels may be increased due to multiple factors, including but not limited to diet, obesity, and insulin resistance conditions such as diabetes or use of certain drugs which are known to interact with polygenic determinants.90,91 Extremely increased TG levels can occur in inherited conditions such as familial chylomicronemia syndrome (FCS, Fredrickson Type I), familial combined hyperlipidemia (Type IIa), dysbetalipoproteinemia or remnant lipoprotein hyperlipidemia (Type III), familial HTG (Type IV), and multifactorial chylomicronemia (MCS, Type V),91-94 as well as in generalized lipodystrophies and familial partial lipodystrophy (LD).95
FCS is an autosomal recessive disorder that affects approximately 1 to 10 individuals per million and is most often caused by pathogenic or likely pathogenic biallelic variants in the LPL gene, which encodes the enzyme lipoprotein lipase (LPL). However, variants in the GPIHBP1, LMF1, APOA5, and APOC2 genes have also been identified as the cause of FCS.96-98 It may also present with two distinct biallelic or digenic variants.
FCS is characterized by an increased risk of recurrent acute pancreatitis.99,100
3.3.1.2. Clinical and Laboratory Diagnosis of Familial Chylomicronemia Syndrome
Clinical manifestations of monogenic forms of chylomicronemia typically occur during childhood or early adulthood. Diagnosis is often delayed and made later in adulthood when complications have already developed.90 Common findings include recurrent abdominal pain (50%),96 recurrent pancreatitis episodes (50%),101 hepatosplenomegaly,102 eruptive xanthomas (17%-33%),96 lipemia retinalis (30%), correlating with higher TG levels.102 Neurological manifestations — such as fatigue, mental confusion, irritability, and cognitive deficits (eg, "mental fog") — are among the most commonly reported symptoms in individuals with FCS, thereby impairing their quality of life.102,103
3.3.1.3. Diagnostic Scores
The score developed by Moulin et al.104 uses the presence of TG levels (> 885 mg/dL fasting and outside the acute phase) as a selection criterion and scores based on increased TG levels and exclusion of secondary causes (Box 3.1). This score has been tested in cohorts of patients with genetically confirmed FCS and in multifactorial chylomicronemia and has been validated in other cohorts. It is recommended for use as a screening tool for genetic testing, or when genetic testing is not available.
3.3.1.4. Differential Diagnosis
In adults, the main differential diagnoses for FCS are MCS92 (Fredrickson type V hyperlipoproteinemia), which includes heterozygous variants in the five canonical genes for FCS or a high polygenic score, aggravated by comorbidities or secondary causes of hypertriglyceridemia (HTG).92 Another differential diagnosis for FCS is LD, characterized by selective loss of adipose tissue, which may present with severe HTG and pancreatitis. Inherited LDs are rare disorders that may manifest at birth (congenital generalized form) or present fat loss later in life. In partial forms, diagnostic suspicion should be considered in the presence of moderate to severe HTG associated with thigh skinfold thickness < 22 mm in women or < 10 mm in men, and/or cases of diabetes requiring subcutaneous insulin at daily doses >2 IU/kg.95
3.3.1.5. Genetic Diagnosis
FCS may be caused by pathogenic or likely pathogenic biallelic variants in the LPL, GPIHBP1, LMF1, APOA5, or APOC2 genes. It may also present with two distinct biallelic variants or in digenic form.105 The genetic panels used include the five canonical genes for FCS as well as genes related to lipodystrophies, cystic fibrosis, pancreatitis, and the LIPA gene, which causes LAL-D.
3.3.1.6. Lipoprotein Lipase Activity
LPL activity is markedly reduced in patients with FCS who carry a biallelic variant in the LPL gene, in those with biallelic loss-of-function variants in other canonical FCS-related genes, or in individuals with digenic variants106. Typically, the activity of this enzyme is reduced to less than 25% in patients with FCS.
3.3.1.7. Other Diagnostic Tests
Autoimmune chylomicronemia may be caused by the presence of anti-GPIHBP1 antibodies, characterized by intermittent HTG and associated with previous autoimmune conditions, including the presence of antinuclear antibodies.107
4. Risk Stratification
4.1. Cardiovascular Risk Stratification
CV risk stratification is the foundation of clinical decision-making in the prevention of CVD, guiding different therapeutic approaches, including the management of LDL-c. Matching the intensity of treatment to the absolute risk of events is essential to ensure benefits for individuals at higher risk and to avoid excessive or unnecessary treatment in those at lower risk.
Although CV risk is a continuous variable, establishing risk categories facilitates the formulation of recommendations and the implementation of the most appropriate treatment (Table 4.1). Accordingly, the current guideline recommends that ASCVD risk be categorized as low, intermediate, high, very high, or extreme (Figure 4.1). Individuals who have already experienced a CV event are considered at the highest risk (very high or extreme risk) (Table 4.1 and 4.2). In the absence of established CVD, the risk category will be determined by the presence or absence of SAD on imaging and by numerous risk factors (both traditional and enhancers). Individuals with type 2 diabetes mellitus (T2DM) require distinct risk stratification due to the high atherogenic potential of T2DM. Similarly, recognizing the role of lifelong exposure to atherogenic lipoproteins in predisposing to events, the current guideline recommends that individuals with LDL-c ≥ 190 mg/dL be classified as high risk, while those with LDL-c between 160 and 189 mg/dL be considered at intermediate risk. For adults with no prior CV events or SAD, without diabetes and with LDL-c < 160 mg/dL, ASCVD risk categorization can be defined using risk equations or scores.
ASCVD risk stratification. AAA: abdominal aortic aneurysm; ASCVD: atherosclerotic cardiovascular disease; AU: Agatston units; CAC: coronary artery calcium score; CKD: chronic kidney disease; CV: cardiovascular; eGFR: estimated glomerular filtration rate; FH: familial hypercholesterolemia; LDL-c: low-density lipoprotein cholesterol; PAD: peripheral arterial disease; MI: myocardial infarction.
4.2. Cardiovascular Risk Scores
CV risk scores are used to estimate the risk of a CV event over a specific time frame. Although many CV risk scores have been developed in different regions of the world, we still lack a score derived from Brazilian population data. Some scores, such as the World Health Organization108 and Globorisk-LAC2 scores,109 have the advantage of being calibrated for the Brazilian population and can be used for assessing CV risk.
In the United States, a new risk equation — the Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) score — was published in 2024 (https://professional.heart.org/en/guidelines-and-statements/prevent-calculator), derived from over 3 million individuals from various cohorts and validated in another 3 million individuals. This score is intended for individuals aged 30 to 79 years without prior cardiovascular disease. In addition to traditional risk factors (sex, age, total cholesterol, HDL-c, systolic blood pressure, use of antihypertensive medication, diabetes, and smoking), it incorporates statin use, body mass index (BMI), and estimated glomerular filtration rate (eGFR), with optional variables including glycated hemoglobin (HbA1c) and urinary albumin-to-creatinine ratio. The Predicting Risk of cardiovascular disease EVENTs (PREVENT) score estimates the 10-year and 30-year risk of ASCVD events (eg, coronary death, nonfatal MI, or stroke), heart failure (HF), and total CV risk. The base model of PREVENT equations for atherosclerotic risk demonstrated satisfactory discrimination in the validation sample (C-statistic 0.774 for women and 0.736 for men).110,111 Because of its robustness and contemporaneity, and in the absence of a risk equation derived from the Brazilian population, the current guideline recommends the use of PREVENT to assess 10-year ASCVD risk to define the need for lipid-lowering therapy.
4.3. Cardiovascular Risk Enhancers
Risk enhancers are markers not included in traditional scores that provide additional information to refine the assessment of CV risk, which may aid clinical decision-making. They are particularly useful in cases where there is uncertainty about the best medical course of action. These factors can be identified from medical history or complementary exams (Table 4.3), and their performance in risk assessment can be determined by metrics such as the area under the receiver operating characteristic (ROC) curve (discrimination) or risk reclassification indices. The use of risk enhancers in clinical practice requires critical judgment: the greater the number and intensity of risk enhancers, the more appropriate it is to reclassify the individual into a higher risk category (Figure 4.2). Individuals with an intermediate calculated risk benefit the most from using risk enhancers, as this is the group in which risk reclassification occurs most frequently. Therefore, active screening for additional risk enhancers is recommended in this population. Nevertheless, risk enhancers can also be used in individuals with a low estimated 10-year risk, especially from a lifetime risk perspective.
Schematic representation of the use of risk enhancers in the assessment of CV risk. Risk enhancers should be incorporated into the continuum of CV risk. The greater the number and the severity of the alterations, the greater the upward adjustment of risk compared to that estimated by traditional scores.
4.3.1. Family History of Premature Cardiovascular Disease
Compared with participants without a parental history of CVD, those with at least one parent with premature CVD (onset age < 55 years in the father or < 65 years in the mother) had a higher risk of events, with an adjusted odds ratio (OR) of 2.0 (95% CI, 1.2-3.1) for men and 1.7 (95% CI, 0.9-3.1) for women.112
4.3.2. Adiposity and its Manifestations
Obesity, defined by a BMI ≥ 30 kg/m2, is consistently associated with an increased risk of major CV events, including CAD, HF, and stroke. Meta-analyses of large populations have shown that individuals with overweight or obesity have a significantly higher risk of developing CAD and CV mortality.113 This risk is even higher in individuals with diabetes or MetS.
Visceral obesity, assessed by waist circumference (WC), is significantly associated with an increased risk of major CV events. WC is a robust measure of central adiposity and represents a relevant CV risk factor independent of BMI.114 Meta-analyses of cohort studies have shown that a 1 standard deviation increase in WC (approximately 12.6 cm) is associated with a hazard ratio (HR) of 1.27 (95% CI, 1.20-1.33) for fatal and nonfatal CV events, adjusted for age, sex, and smoking.115 This risk is observed across different populations and in both sexes, being slightly higher in women. These data reinforce the importance of WC as a key parameter in the assessment and management of CV risk. The current concept of adiposity is defined by an elevated BMI associated with one elevated anthropometric parameter (waist circumference, waist-to-hip ratio, or waist-to-height ratio) or with two elevated anthropometric parameters.116,117
Visceral obesity is strongly associated with the manifestation of MetS and steatosis, including hepatic steatosis. When considered independently, MetS is a well-established risk enhancer for major CV events in individuals without prior CVD. MetS is characterized by a cluster of abnormalities — increased WC, increased TG, decreased HDL-c, increased blood pressure, and increased fasting glucose — that together increase the risk of ASCVD. Several meta-analyses have shown that MetS is associated with a twofold increased risk of CVD and a 1.5-fold increased risk of all-cause mortality, regardless of the definition used.118
Hepatic steatosis, especially in the form of metabolic dysfunction–associated steatotic liver disease (MASLD), is consistently associated with an increased risk of major CV events. Several cohort studies have demonstrated that individuals with MASLD or nonalcoholic fatty liver disease (NAFLD) have higher HRs for MI, stroke, congestive HF, and overall CVD compared to those with no steatosis. Adjusted HRs range from 1.12 to 1.75, with stronger associations observed in patients with histological confirmation of the disease or hepatic steatosis independent of CAD characteristics. Some meta-analyses support this association.119
In summary, the association between obesity and CV risk is well established and becomes more significant with the development of visceral obesity, steatosis, and MetS. The link with atherogenesis occurs through multiple and overlapping mechanisms among these manifestations. Therefore, we consider MetS a risk enhancer for reclassification, while the other findings help define the clinical condition related to obesity and the effectiveness of interventions targeting obesity or steatosis.
4.3.3. Chronic Inflammatory Conditions
Several chronic inflammatory and autoimmune conditions — such as rheumatoid arthritis,120 psoriasis,121 systemic lupus erythematosus,122 inflammatory bowel diseases (IBDs) (eg, ulcerative colitis and Crohn's disease),123 and chronic HIV infection124 — are independently associated with an increased risk of various manifestations of CVD, including atherosclerosis. The proposed mechanisms are diverse and involve not only the frequent coexistence of classical risk factors and the adverse effects of treatments, but also a systemic pro-inflammatory state that promotes endothelial dysfunction and accelerates atherogenesis.
For example, a meta-analysis including over 500,000 cases and nearly 30 million controls found that psoriasis was associated with overall CVD (OR, 1.4; 95% CI, 1.2-1.7), ischemic heart disease (OR, 1.5; 95% CI, 1.2-1.9), and peripheral vascular disease (OR, 1.5; 95%, CI 1.2-1.8).125 In the case of people living with HIV, a large systematic review showed a HR of 2.16 (95% CI, 1.68-2.77) for developing CVD compared to individuals without HIV.126 Thus, traditional CV risk equations may underestimate the actual risk in people with inflammatory and autoimmune diseases, supporting their inclusion among risk enhancers.
4.3.4. Organ Transplantation
Individuals who undergo organ transplantation — such as heart, liver, or kidney — are at increased risk of various forms of CVD, including CAD, compared with the general population. The mechanisms appear to be multifactorial: frequent presence of traditional risk factors (hypertension, diabetes, dyslipidemia), metabolic effects of immunosuppressive agents like corticosteroids, chronic inflammation, and immune activation leading to endothelial dysfunction, accelerated atherosclerosis, and a prothrombotic state.127 Such observations support considering post-transplantation status as a CV risk enhancer.
4.3.5. Women-Specific Cardiovascular Risk-Enhancing Factors
The current guideline emphasizes the importance of considering several women-specific factors in the assessment of CV risk.
4.3.5.1. Age at Menarche
Age at menarche is a nontraditional but relevant CV risk factor in women. Both early menarche (commonly defined as ≤ 12 years) and late menarche (≥ 17 years) are associated with an increased risk of CV events and all-cause mortality, with stronger evidence supporting the risk associated with early menarche.128
4.3.5.2. Pregnancy-Related Disorders and Preterm Birth
Hypertensive disorders of pregnancy (preeclampsia, eclampsia, and gestational hypertension), gestational diabetes, preterm birth, and intrauterine growth restriction are associated with increased future CV risk. A meta-analysis of data from more than 6.4 million women (258,000 with preeclampsia) demonstrated that preeclampsia was independently associated with a 4-fold higher risk of incident HF and a 2-fold higher risk of CAD. Similarly, women with gestational diabetes have a 2-fold increased risk of CV events (HR, 1.98; 95% CI, 1.57-2.50).129
Preterm birth has an immediate physical and emotional impact and is associated with increased maternal risk of hospitalization for CVDs, including MI, stroke, and other CV admissions.130
4.3.5.3. Recurrent Miscarriages
Recurrent miscarriages (three or more spontaneous pregnancy losses) are associated with a significant long-term increase in maternal CV risk, including CAD, stroke, and hypertension. The risk is more pronounced in younger women (< 35 years) and increases progressively with the number of losses.131 Therefore, a history of recurrent miscarriages should be considered an independent marker of CV risk in women, warranting clinical vigilance and early preventive interventions to address traditional risk factors and provide ongoing cardiometabolic follow-up.
4.3.5.4. Premature Menopause
Premature menopause (defined as menopause before age 45, and especially before age 40) is associated with an increased risk of CVDs such as CAD, HF, stroke, PAD, and major CV events.132 It should be incorporated into risk stratification and decision-making regarding preventive interventions.
4.4. Additional Tests
4.4.1. Lipoprotein(a)
The association between Lp(a) and CV risk is well documented in several prospective cohort studies. The ERFC (Emerging Risk Factors Collaboration) study analyzed the impact of increased Lp(a) on CV event risk in individuals without previous CVD. The coronary event rates in the highest and lowest thirds of Lp(a) distribution were 5.6 (95% CI, 5.4-5.9) and 4.4 (95% CI, 4.2-4.6) per 1,000 person-years, respectively. The HR for coronary events, adjusted only for age and sex, was 1.16 (95% CI, 1.11-1.22) for a 3.5-fold higher usual Lp(a) level (equivalent to 1 standard deviation increase), and 1.13 (95% CI, 1.09-1.18) after further adjustment for lipids and other conventional risk factors. Adjusted HRs were 1.10 (95% CI, 1.02-1.18) for ischemic stroke and 1.01 (95% CI, 0.98-1.05) for nonvascular mortality.133 Data from another UK cohort (UK Biobank) showed a linear association between Lp(a) and ASCVD across the entire distribution, with an HR of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increase.64
An Lp(a) level ≥ 50 mg/dL or 125 nmol/L indicates a risk enhancer, raising risk classification from low to intermediate or from intermediate to high. Very high levels, > 180 mg/dL or 390 nmol/L, indicate a high risk of CV events.65
4.4.2. High-Sensitivity C-Reactive Protein
Inflammation plays a central role in the pathophysiology of ASCVD. Serum C-reactive protein (CRP), especially when measured by high-sensitivity assays, is a biomarker of systemic inflammation associated with CV outcomes, including MI and stroke, in numerous epidemiological studies. In the Framingham Offspring study, high-sensitivity CRP (hs-CRP) improved net reclassification beyond traditional risk factors by 5.6% for CV events (p = 0.014) and 11.8% for coronary events (p = 0.009).134 A systematic review reported that analyses from four large cohorts consistently found evidence that including hs-CRP improves risk stratification among individuals initially classified as intermediate risk.135 Therefore, the guideline recommends considering hs-CRP ≥ 2.0 mg/L as a CV risk enhancer.
A recent analysis from the Women's Health Study, which evaluated approximately 27,000 initially healthy women, showed that a single combined measurement of high-sensitivity CRP, LDL-c, and Lp(a) was predictive of incident cardiovascular events during a 30-year period. This finding suggests that the use of these biomarkers can aid in lifelong risk stratification, potentially adding value to traditional risk assessment models.136
Two subsequent large studies confirmed the predictive power of this combination of biomarkers in both men and women, regardless of lipid-lowering therapy use.137,138
Beyond the risk prediction potential of these three combined parameters, the demonstrated benefit from reducing their concentrations [with the cardiovascular benefit of lowering Lp(a) concentrations still yet to be demonstrated] suggests the importance of initiating early preventive strategies when these variables are elevated.
4.4.3. High-Sensitivity Cardiac Troponins
Cardiac troponins I and T are specific circulating biomarkers with a well-established role in the diagnosis and prognosis of ACS. In individuals with chronic coronary syndrome and in the general population, high-sensitivity cardiac troponin (hs-cTn) assays can detect low-grade MI with prognostic value. Several prospective observational studies in healthy populations have demonstrated that increased hs-cTn levels, even within the normal range, are independently associated with CV outcomes, including CV death, CAD, and stroke,139 providing incremental value to risk stratification beyond traditional risk factors.140 Hs-cTn can also be used in conjunction with CAC. In MESA (Multi-Ethnic Study of Atherosclerosis), the incidence of atherosclerotic events was similar in individuals with undetectable hs-cTn and CAC = 0 at baseline, while those with detectable hs-cTn and CAC > 0 had the highest event rate (HR 3.50 compared to the reference group with undetectable hs-cTn and CAC = 0).141
Although promising, the use of hs-cTn for CV risk stratification in healthy individuals has important limitations. Since serum concentrations of hs-cTn are very low (in the order of pg/mL), significant variations may occur within the normal range due to assay imprecision. Physiological variations related to sex and age are also observed, with generally higher values in men and in the elderly. In addition, a clear cutoff value to accurately distinguish individuals at higher or lower CV risk has not been established, although some proposals exist. For a specific hs-cTn assay brand, Farmakis et al. suggested defining high risk when hs-cTnI is > 12 ng/L in men or > 10 ng/L in women, low risk when < 6 ng/L in men or < 4 ng/L in women, and intermediate risk for values between these limits.139
4.4.4. B-Type Natriuretic Peptide and N-Terminal Pro-B-Type Natriuretic Peptide
Prospective population-based studies have shown that increased levels of B-type natriuretic peptide (BNP) or its N-terminal fragment (NT-proBNP) predict increased risk of a wide range of clinical outcomes, including all-cause mortality, CV mortality, HF, atrial fibrillation, stroke, transient ischemic attack (TIA), and the composite outcome of CAD and stroke, independently of other risk factors.142,143 NT-proBNP has also demonstrated incremental value in CV risk discrimination and reclassification when added to models based on traditional risk factors.143 However, well-defined thresholds for re-stratifying risk based on NT-proBNP levels are still lacking. Likewise, no RCTs guide therapeutic interventions based on this biomarker, nor are there cost-effectiveness studies supporting its routine use in clinical practice. Since the association between BNP and CV outcomes is stronger for HF and that its relationship with coronary events is not always evident,142 the current guideline does not recommend measuring BNP or NT-proBNP for ASCVD risk stratification in asymptomatic individuals or those without established CVD.
4.5. Markers of Subclinical Atherosclerotic Disease
Imaging tests that demonstrate the presence of SAD can be used as evidence of ongoing ASCVD. Naturally, varying degrees of this presentation exist along a continuum, and the greater the presence and burden of subclinical disease, the higher the risk of CV events. The two main tools for detecting SAD are CAC scoring and carotid artery ultrasound with assessment of carotid plaque presence. CAC can be objectively quantified via coronary artery computed tomography. Carotid plaque presence, for which various definitions exist in the literature, may depend on operator evaluation.
4.5.1. Coronary Artery Calcium Score
CAC reflects the calcified component of atherosclerotic plaque in the coronary arteries. The higher the CAC score, the greater the total plaque burden and the higher the risk of ASCVD events. Absence of CAC (CAC = 0) is a strong negative predictor of CV risk and is associated with low rates of CV events and mortality over 10 years. The favorable prognosis of CAC = 0 is observed even in older individuals or those with multiple risk factors, although it is less evident in individuals with diabetes, smokers, or those with a family history of premature ASCVD.144 On the other hand, individuals with CAC > 300 Agatston units (AU) have a CV event risk similar to those with a prior clinical atherosclerotic event145 and should therefore be classified as very high risk. Individuals with CAC > 100 AU or above the 75th percentile for age and sex should be considered at high risk. Among patients with FH, CAC > 100 AU indicates very high risk (Table 4.4).
A systematic review and meta-analysis was conducted, including studies that assessed the performance of CAC compared to traditional risk scores. Regardless of the modeling approach, the meta-analysis showed a consistent association between higher CAC scores and increased risk of CV events. The addition of CAC to traditional risk scores improved risk discrimination by 0.04 units compared to using traditional scores alone (mean difference [MD], 0.04; 95% CI, 0.01-0.06; I2 = 0%; p = 0.0033; moderate certainty of evidence; Figure 4.3).146 The outcome of risk reclassification with the inclusion of CAC in traditional cardiovascular risk scores was evaluated in six studies using the net reclassification improvement (NRI). Adding CAC to traditional scores increased risk reclassification by 0.33 units (scale from 0 to 1), compared with traditional scores alone (MD, 0.33; 95% CI, 0.17–0.49; I² = 87.5%; p < 0.001; moderate certainty of evidence; Figure 4.4). Such findings support the recommendation to use CAC when available in individuals over 40 years of age with LDL-c levels between 70-159 mg/dL and an intermediate calculated risk (or even low risk with a family history of premature ASCVD), to guide the need for and intensity of lipid-lowering therapy.146
Meta-analysis evaluating the change in C-statistic with the addition of the CAC score to the traditional CV risk score for MACE.146 CAC: coronary artery calcium; CV: cardiovascular; MACE: major adverse CV events.
Meta-analysis evaluating risk reclassification with the addition of the CAC score to the traditional CV risk score.146 CAC: coronary artery calcium; CV: cardiovascular.
Although cost-effectiveness studies conducted in the United Kingdom, Canada,147 and the United States148 recommend the use of CAC in intermediate-risk patients (10-year risk by pooled cohort equations of 5%-7.5% or by QRISK3 of 10%-20%) and advocate high-intensity statin use in patients with CAC ≥ 1 and no statin use in those with CAC = 0, a Brazilian study suggests the use of moderate-intensity statins in patients with CAC ≥ 1, using the MESA study population and microsimulation based on Brazilian costs.149
4.5.2. Carotid Artery Ultrasound
As a tool with very low risk and relative availability, ultrasound of different arterial beds, such as the carotid and lower limb arteries, can be used to detect SAD.150-152 For CV risk prediction, the most studied modality is carotid artery ultrasound, which allows the analysis of two main variables: carotid intima-media thickness (CIMT) and the presence of atherosclerotic plaque. Carotid plaque may be defined by the following criteria: (1) any focal thickening considered of atherosclerotic origin that invades the lumen of any segment of the carotid artery (protruding plaque type); or (2) in the case of diffuse atherosclerosis of the vessel wall, when CIMT is ≥ 1.5 mm in any carotid artery segment (diffuse plaque type).150
A meta-analysis of 14 studies showed that a 1-standard-deviation increase in common carotid CIMT was associated with increased risk of stroke (HR, 1.32; 95% CI, 1.27-1.38), MI (HR, 1.27; 95% CI, 1.22-1.33), and the composite outcome of stroke and MI (HR, 1.28; 95% CI, 1.19-1.37). However, the ability of CIMT to discriminate risk beyond Framingham risk score factors was not relevant (C-statistic increased from 0.757 to 0.759), and the NRI was low: 0.8% for the general population and 3.6% for the intermediate-risk population.151 Since the lack of standardization in the measurement of CIMT and its low risk reclassification power, there is currently no evidence to support the clinical use of CIMT as a risk enhancer.
On the other hand, the presence of carotid plaque in asymptomatic individuals is a better predictor of CV events than CIMT. A meta-analysis of 11 population-based studies showed that carotid plaque outperformed CIMT in predicting MI (ROC AUC 0.64 vs. 0.61).152 A Swedish cohort analysis showed that the improvement in C-statistic and NRI with the addition of plaque to SCORE2 for 10-year events was 2.20% and 46.1%, respectively (both p < 0.0001).153 Therefore, the presence of carotid plaque provides incremental information beyond clinical risk scores alone.
4.6. Cardiovascular Risk Stratification in Diabetes
T2DM is associated with a 2fold higher CV risk compared to the population without T2DM. It is an independent risk factor not only for ASCVDs such as MI and ischemic stroke, but also for HF and atrial fibrillation.154,155 In assessing CV risk in individuals with T2DM, in addition to traditional risk factors, T2DM-specific variables should be considered, such as disease duration (risk substantially increases when ≥ 10 years), HbA1c levels, and the presence of target organ damage. The current guideline proposes a classification of CV risk in individuals with T2DM into four categories (intermediate, high, very high, and extreme risk), based on the patient's age and the presence or absence of risk stratifiers or extreme risk criteria (Tables 4.5, 4.6, 4.7 and 4.8).
For individuals with type 1 diabetes mellitus (T1DM) with less than 20 years of disease duration and without risk stratifiers or extreme risk criteria, the current guideline recommends the use of the Steno Type 1 Risk Engine to predict a first CV event (https://steno.shinyapps.io/T1RiskEngine/)156 (Table 4.5).
4.7. Categories of Atherosclerotic Cardiovascular Risk
The current guideline recommends moving away from the binary classification of "primary prevention" and "secondary prevention" and instead recognizing CV risk along a so-called risk continuum. In this approach, CV risk is viewed as a continuous variable, ranging from one end — representing low risk in a young individual without a history of CV events and without risk factors — to the other extreme, which represents individuals with multiple recurrent CV events (see Central Illustration).
The definitions of the risk categories recommended in the current guideline are presented in Table 4.3.
4.8. Particularities of Cardiovascular Risk Stratification in Older Adults
CV risk assessment in older adults has some specific considerations. First, it is well recognized that the strength of the association between risk factors and CV events weakens with aging. On the other hand, since age is the factor with the greatest weight in determining risk, the absolute risk of CV events increases with age. Second, older risk scores did not account for the competing risk of death from nonCV causes, which often led to overestimation of risk and consequently of the predicted benefit of therapeutic interventions in older individuals. Third, most risk equations were developed for populations under 80 years old. PREVENT, for example, is intended for individuals up to 79 years of age,110,111 although it has shown good performance in older populations in a study.158
In Europe, the SCORE2-OP (Systematic COronary Risk Evaluation 2 for Older Persons) was developed to estimate CV risk in individuals aged ≥ 70 years.159 The score was calibrated for four regions based on the CV mortality rates of European countries, with the rates from moderate-risk areas being the most similar to those observed in Brazil. According to the SCORE2-OP for moderate-risk European regions, the 10-year risk of CV death, nonfatal MI, or nonfatal stroke in individuals aged ≥ 80 years is invariably ≥ 20%, making this population a high-risk subgroup.
4.9. Particularities of Cardiovascular Risk Stratification in Young Adults
Because age is the main determinant of CV risk, young individuals often have a low 10-year risk estimate even when risk factors are poorly controlled. The PREVENT score adopted in the current guideline was not developed for individuals under 30 years of age,110,111 so this age group still lacks a dedicated model for risk assessment. Even lifetime risk estimation models do not include very young individuals: the Lifetime Risk model recommended by the American Heart Association includes individuals starting at age 50,59 and the LIFE-CVD2 model starts at age 35.161
In addition to conventional risk factors, the current guideline recommends evaluating risk enhancers in adults under 30 years of age. Depending on the type and intensity of the risk enhancer, the individual may be reclassified into a higher risk category, especially considering the long-term consequences.
For young adults aged ≥ 30 years, calculating 30-year CV risk by using PREVENT may be appropriate. Although no thresholds are defined for risk categorization, the 30-year estimate can be used to raise awareness of risk factors and motivate patients regarding treatment.
4.10. Cardiovascular Risk Stratification in Childhood and Adolescence
The risk of CVD in children and adolescents can be stratified based on exposure to traditional risk factors (eg, homozygous FH [HoFH] or HeFH, hypertension, severe obesity, and T2DM). In addition, the presence of underlying conditions (eg, T1DM, CKD, childhood cancer treatment, chronic inflammatory conditions such as juvenile idiopathic arthritis [JIA]) may increase vulnerability to the adverse effects of traditional risk factors, justifying aggressive therapies for their control to reduce CV risk.162 The current guideline adopts the risk stratification model proposed by the American Heart Association in 2019, which categorizes children based on underlying diseases162 (Table 4.9).
5. Treatment Targets
5.1. Primary and Co-Primary Target: Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol
Although the defined cholesterol targets have not been systematically tested but derived from randomized controlled trials (RCTs) sub-analyses based on achieved LDL-c levels, we believe that defining clear targets allows for personalized treatment aligned with individual CV risk. Moreover, using targets can facilitate communication between physician and patient, improving adherence and helping to reduce therapeutic inertia (Table 5.1).
Evidence from interventional studies and meta-regressions clearly and unequivocally demonstrates that CV risk is reduced by lowering LDL-c.163-169 This reduction is proportional to the magnitude of LDL-c decrease: for every 39 mg/dL (1 mmol/L) reduction in LDL-c, the relative risk (RR) of major CV events is reduced by approximately 20%-25%, with no evidence of a lower limit below which no additional benefit is observed.166 Thus, the current guideline recommends not only specific targets but also the adoption of a minimum percentage reduction in LDL-c.
Non-HDL-c, obtained by subtracting HDL-c levels from total plasma cholesterol concentration, shows a strong correlation with circulating serum levels of apoB.57,170-172 Therefore, it is considered a more accurate marker of the atherogenic burden associated with lipid-rich lipoproteins than isolated LDL-c concentration, especially in individuals with HTG.171-173 In such cases — where LDL particles are enriched with TG — the cholesterol concentration within LDL particles may be relatively reduced, leading to an underestimation of the total atherogenic burden contributed by both LDL and other atherogenic lipoproteins.174 Therefore, non-HDL-c has been recognized as a more accurate predictor of CV risk in such clinical contexts.175-177 The recommended target for non-HDL-c, aimed at reducing the risk of ASCVD events, is defined as a value 30 mg/dL higher than the LDL-c goal for each CV risk category.55 This parameter is considered an additional therapeutic target to be pursued after achieving the recommended LDL-c target for the respective risk stratum.55
Accordingly, the current guideline sets goals for LDL-c as the primary therapeutic target and for non-HDL-c as a co-primary target, both defined according to the CV risk category.
In line with evidence from RCTs, genetic studies, and epidemiological data, it is recommended to introduce pharmacological therapy in individuals classified as low risk with LDL-c levels persistently above 145 mg/dL, despite lifestyle measures.178-188
Therapeutic intervention recommendations:
-
For individuals at low to intermediate risk: a reduction in LDL-c of 30% or more is recommended.
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For individuals at high, very high, or extreme risk: the therapeutic goal is a reduction in LDL-c of 50% or more.
High-potency statins or combination therapy are preferably recommended. Because of the interindividual variability in response to statins,189 it is often necessary to combine them with other lipid-lowering agents to achieve the proposed targets.
5.2. Recommendations for Targets According to Cardiovascular Risk Stratification (Figure 5.1)
5.2.1 Individuals at Intermediate Risk
A meta-analysis based on individual patient data from RCTs with statins showed that in individuals categorized as low risk, there was an absolute reduction of 11 major CV events per 1,000 people for every 38.7 mg/dL reduction in LDL-c over 5 years. This benefit far outweighs any inherent risks associated with statin therapy.190
Even if stratified as low risk, individuals who maintain LDL-c ≥ 145 mg/dL despite lifestyle modifications, excluding secondary causes, qualify for initiation of lipid-lowering therapy.178-188
In this context, it is recommended:
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LDL-cdecrease ≥ 30%
-
Primary LDL-c target: < 115 mg/dL
-
Co-primary non-HDL-c target: < 145 mg/dL
5.2.2. Individuals at Intermediate Risk
In this context, it is recommended:
-
LDL-c decrease ≥ 30%
-
Primary LDL-c target: < 100 mg/dL
-
Co-primary non-HDL-c target: < 130 mg/dL
5.2.3. Individuals at high risk
For individuals classified as high CV risk, the current guideline recommends high-intensity lipid-lowering therapy. Therefore, the preferential use of high-potency statins or combination therapy (statin plus ezetimibe) is recommended.
In this context, it is recommended:
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LDL-c reduction ≥ 50%
-
Primary LDL-c target: < 70 mg/dL
-
Co-primary non-HDL-c target: < 100 mg/dL
5.2.4. Individuals at Very High Risk
The LDL-c target is < 50 mg/dL and the non-HDL-c target is < 80 mg/dL. This recommendation is primarily based on the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study, in which combination therapy with simvastatin and ezetimibe, reaching a mean LDL-c of 53 mg/dL, resulted in a further decrease in CV risk compared to monotherapy (mean LDL-c of 69 mg/dL).165
In patients with established ASCVD — and therefore at very high CV risk — the combination of moderate-potency statin and ezetimibe has been shown to be noninferior to high-potency statin monotherapy in reducing CV events. In the same study, combination therapy was associated with a higher rate of achieving recommended LDL-c targets and a lower rate of lipid-lowering therapy discontinuation due to intolerance.191 Subsequent evidence showed additional CV risk reduction with the addition of PCSK9 inhibitors in individuals with ASCVD and residual dyslipidemia despite statin therapy, with or without ezetimibe. In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, LDL-c decrease mediated by evolocumab (median level of 30 mg/dL) reduced the RR of major CV events by 15% after a median follow-up of 2.2 years.168 In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, alirocumab use in patients post-ACS (1 to 12 months prior to randomization) reduced LDL-c to a median of 53 mg/dL, resulting in a 15% RR decrease in clinically relevant CV outcomes after a median follow-up of 2.8 years.169
In this context, it is recommended:
-
LDL-c decrease ≥ 50%
-
Primary LDL-c target: < 50 mg/dL
-
Co-primary non-HDL-c target: < 80 mg/dL
5.2.5. Individuals at Extreme Risk
Patients with ASCVD, even after an ACS, have a variable residual risk for new CV outcomes. A sub-analysis of the ODYSSEY OUTCOMES trial, which stratified participants according to the risk categorization proposed by the ACC/AHA Dyslipidemia Guideline, showed a CV event rate of 20.4% in the subgroup with a history of multiple prior events, compared to 5.6% among those without high-risk criteria.192 Similarly, several sub-analyses of the FOURIER trial revealed a higher incidence of CV events in subgroups with high-risk features such as extensive coronary disease, multiple prior CV events, increased Lp(a), presence of diabetes, PAD, and multivessel disease. As expected, considering that the absolute benefit of therapeutic intervention is proportional to baseline risk, these patients experienced greater clinical benefit when achieving more stringent lipid targets and using higher-cost therapies193-197 — reflected in lower number needed to treat and, consequently, improved cost-effectiveness. A secondary analysis of the FOURIER trial demonstrated a monotonic linear relationship between achieved LDL-c levels and incidence of adverse CV events, with progressive risk reduction observed down to serum concentrations below 20 mg/dL. Such findings reinforce the principle that in CV prevention, "the lower the LDL-c, the better."198 Moreover, to date, there is no consistent evidence of adverse events associated with very low LDL-c levels.199-203 Thus, the current guideline recommends more stringent therapeutic targets for individuals classified as being at extreme CV risk: LDL-c < 40 mg/dL and non-HDL-c < 70 mg/dL.
In this context, it is recommended:
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LDL-c reduction ≥ 50%
-
Primary LDL-c target: > 40 mg/dL
-
Co-primary non-HDL-c target: < 70 mg/dL
5.3. Apolipoprotein B
Measurement of serum ApoB levels is widely recognized as the most accurate indicator of CV risk associated with atherogenic lipoproteins. This is because each potentially atherogenic lipoprotein particle circulating in the bloodstream — including LDL, VLDL, Lp(a), VLDL remnants, and chylomicrons — contains exactly one ApoB molecule. Thus, direct quantification of ApoB accurately reflects the total number of circulating atherogenic particles. Furthermore, its measurement does not require fasting, which facilitates its clinical use. Notably, chylomicrons contain a truncated isoform of ApoB, ApoB-48, while the other atherogenic particles contain ApoB-100.7,59,204,205
Currently, ApoB testing is not covered by most health insurance plans and is also not available through the SUS. As a viable alternative, the measurement of non-HDL-c shows good correlation with serum ApoB levels and can be easily obtained from any standard lipid panel, since it only requires subtracting HDL-c from total cholesterol. This approach represents a practical, accessible tool for estimating atherogenic burden in clinical settings where the direct measurement of ApoB is unavailable.57,170,171 However, ApoB targets may be used for additional stratification in patients who have already achieved their LDL-c and non-HDL-c targets. The equivalence between LDL-c and ApoB targets206 is shown below:
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LDL-c 40 mg/dL ≈ ApoB 45 mg/dL
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LDL-c 50 mg/dL ≈ ApoB 55 mg/dL
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LDL-c 70 mg/dL ≈ ApoB 70 mg/dL
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LDL-c 100 mg/dL ≈ ApoB 90 mg/dL
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LDL-c 115 mg/dL ≈ ApoB 100 mg/dL
5.4. High-Density Lipoprotein Cholesterol
No specific therapeutic targets are proposed for HDL-c. Although epidemiological studies have shown a strong association between low HDL-c levels and a higher incidence of CV events,207 there is no robust evidence indicating that this relationship is causal. In Mendelian randomization studies, individuals genetically predisposed to higher HDL-c levels did not present a reduced risk of atherosclerosis.208 Moreover, therapies aimed at increasing HDL-c levels have not demonstrated consistent benefits in reducing CV events.209-214 Thus, HDL-c should be used as a CV risk marker but not as a therapeutic target.
5.5. Triglycerides
TG-rich lipoproteins and particularly their metabolic remnants contribute to the residual risk of ASCVD. Serum TG concentration is a marker of atherosclerotic residual risk,215,216 and tends to increase alongside the prevalence of conditions such as obesity and T2DM, in which TG levels are often mildly to moderately increased.217,218
Fasting serum TG levels ≥ 150 mg/dL or postprandial TG levels ≥ 175 mg/dL are considered abnormal,173 e and the recommended target is to maintain levels below these thresholds. However, bear in mind that LDL-c and non-HDL-c targets are more important for patients with mild to moderate HTG.91
Besides lifestyle modifications, which are effective in lowering TG, the current guideline recommends, when pharmacological therapy is necessary, the preferential use of agents targeting non-HDL-c decrease, such as high-intensity statins and ezetimibe. Proper glycemic control contributes to lowering serum levels of TG. In this regard, glucose-lowering agents with proven CV benefits, such as SGLT2 inhibitors and GLP-1 receptor agonists (GLP-1 RAs), may be used to simultaneously manage glycemia and reduce CV risk. Even in nondiabetic individuals, high doses of a GLP-1 RA (semaglutide 2.4 mg) have been shown to reduce TG and CV risk in patients with established CVD and overweight or obesity.219
Severe HTG, defined as serum levels of TG ≥ 500 mg/dL (or ≥ 885 mg/dL according to many authors), is associated with an increased risk of acute pancreatitis. In such cases, more potent TG-lowering agents, such as fibrates, are recommended, with the therapeutic goal of keeping levels < 500 mg/dL.
5.6. Lipoprotein(a)
Currently, no treatment is specifically approved to lower serum levels of Lp(a). Ongoing phase 3 prospective studies may provide consistent data on the relationship between the degree of Lp(a) decrease and its effect on CV outcomes in patients at high or very high risk.220
Nevertheless, the current guideline reinforces the importance of assessing the levels of Lp(a) at least once in a lifetime for all individuals. Even though the impact of Lp(a) decrease on CV risk remains uncertain and therapeutic targets have not yet been defined, the documentation of increased levels of Lp(a) may assist in CV risk stratification,221,222 thus supporting the adoption or intensification of strategies aimed at controlling other modifiable risk factors.
6. Nonpharmacological Treatment
6.1. Lifestyle Recommendations to Improve Lipid Profile
6.1.1. Nutritional Aspects
The recent trend is to emphasize a qualitative rather than a quantitative approach to macronutrients, prioritizing minimally processed, fiber-rich dietary patterns, and reducing the intake of added sugars and refined carbohydrates.223
See below for evidence regarding the main dietary macronutrients:
6.1.2. Carbohydrates
In the PURE study, a high carbohydrate intake (> 60% of total energy) was associated with increased all-cause mortality.224 Similarly, the ARIC (Atherosclerosis Risk in Communities) study showed that diets providing 50%-55% of total energy from carbohydrates were associated with lower total mortality risk, whereas diets high in refined carbohydrates (eg, sugars and processed flours) were linked to increased risk of CVD and metabolic diseases.224,225 As demonstrated in a recent meta-analysis of prospective cohorts, extreme diets (< 40% or > 65% of energy from carbohydrates) were associated with higher overall mortality.226
It is recommended to reduce or eliminate added sugars and refined flours224,226 and to prioritize foods with a low glycemic index (eg, legumes, whole grains, fruits with peel) and fiber-rich carbohydrate sources.227
6.1.3. Fats
Replacing saturated fats with unsaturated fats, such as monounsaturated (eg, olive oil, avocado) and polyunsaturated fats (eg, fatty fish, flax seeds), has been shown to reduce LDL-c and prevent CVD. Conversely, replacing saturated fats with refined carbohydrates tends to increase TG levels and lower HDL-c, both of which are also associated with increased CV risk.55,228,229
6.1.4. Soluble Fiber
Soluble fibers are characterized by their ability to absorb water and form a viscous gel in the gastrointestinal tract, which inhibits micelle formation and delays gastric emptying. This leads to reduced cholesterol absorption, increased bile acid excretion, and modulation of the gut microbiota, resulting in significant cholesterol-lowering effects.230-232
The recommendation is a minimum intake of 25 g/day of total fiber,233 including sources such as β-glucan (oats),231 psyllium, legumes, and fruits with peel.
6.2. Smoking Cessation
Smoking accounts for 50% of all preventable deaths among smokers, with half of these being related to ASCVD.234 The risk of ASCVD in smokers under 50 years of age is five times higher than in nonsmokers and is associated with a higher incidence of stroke, PAD, and sudden cardiac death.235 Smoking contributes to the development of atherosclerosis through multiple pathophysiological mechanisms: endothelial dysfunction due to reduced bioavailability of endothelial nitric oxide (NO); increased production of reactive oxygen species (ROS), which promotes LDL-c oxidation; increased circulating levels of inflammatory markers and stimulation of a prothrombotic state; and a decrease in HDL-c levels.236,237 Smoking cessation provides immediate and progressive CV benefits, regardless of age or smoking duration. After 1 year of smoking abstinence, the risk of MI decreases by 50%.238
The approach should be multifactorial and include both behavioral and pharmacological strategies. Individual or group counseling programs are effective in reducing smoking rates. The indication of pharmacological treatment depends on the patient's level of nicotine dependence, which can be assessed using the Fagerström test.239 This approach includes nicotine replacement therapy (NRT) using patches, gums, and lozenges. Bupropion, a dopamine and norepinephrine reuptake inhibitor, helps reduce withdrawal symptoms, contributing to more effective management.
6.3. Management of Weight
In individuals with obesity, the lipid profile is typically characterized by increased TG, low HDL-c, and small, dense, pro-atherogenic LDL-c particles. These factors, combined with increased visceral fat and insulin resistance, place many patients within the criteria for MetS.240
Nonpharmacological treatment of obesity requires a continuous, patient-centered approach. Multidisciplinary behavioral interventions must last at least 6 months to promote lifestyle changes. Weight loss of 8%-10% is directly associated with a reduction of 5-10 mg/dL in LDL-c, 20-30 mg/dL in TG, and an increase of 3-5 mg/dL in HDL-c.240,241 These findings were also supported by the Look AHEAD trial,242 which included patients with diabetes, overweight, or obesity. A weight loss of 5%-10% within 1 year was associated with a 40 mg/dL decrease in TG and a 5 mg/dL increase in HDL-c. However, LDL-c decrease was modest and not statistically significant. Long-term weight maintenance remains challenging, with recurrent weight regain observed after 2 years of follow-up.243
The adoption of healthy eating habits from childhood helps prevent obesity and related chronic diseases.244 Recent studies have focused on various diets and behaviors, particularly caloric restriction strategies, which have proven effective for weight loss within 6 months.245,246 However, the benefits of weight loss on CV risk factors are mostly observed over the long term.247 Multidisciplinary approaches involving psychologists, nutritionists, physical educators, and mental health professionals have been shown to be effective.248
6.4. Spirituality
A growing body of evidence highlights a strong relationship between spirituality, religiosity, and the processes of health, illness, and healing, forming part of a holistic view of the human being alongside physical, psychological, and social aspects.249 Spirituality and religiosity are often used by patients to cope with illness and suffering. Understanding their relevance, identifying needs, and providing appropriate spiritual and religious support benefit not only patients, but also the multidisciplinary team and the health care system as a whole. Spirituality is expressed through beliefs, values, traditions, and practices.250
Scientific evidence shows that religiosity/spirituality is associated with lower prevalence of smoking, alcohol consumption, and physical inactivity, and with better nutritional and pharmacological adherence in individuals with dyslipidemia, hypertension, obesity, and diabetes.251,252
6.5. Physical Activity
Sedentary behavior is associated with an increased risk of several major chronic diseases and mortality, while physical activity is an essential component in the prevention and treatment of CVD.253 Its impact on lipids is primarily seen through increases in HDL-c and a moderate benefit in the levels of LDL-c, although changes in the absolute levels of LDL-c are less pronounced.254 Additionally, there is a consistent reduction in plasma levels of TG.255
Adults should perform at least 150 minutes/week of moderate-intensity aerobic activity or 75 minutes of vigorous activity and can benefit from combining both.256
Resistance training is associated with lower risks of CV events and all-cause mortality. It is recommended to perform 1 to 3 sets of 8-12 repetitions at 60%-80% of 1-repetition maximum (1-RM), at least twice per week, across 8-10 exercises targeting all major muscle groups.256
For older adults or deconditioned individuals, it is recommended to start with 1 set of 10–15 repetitions at 40%–50% of one-repetition maximum (1-RM). In addition, older adults should engage in multicomponent physical activity that includes aerobic, muscle-strengthening, and balance exercises to prevent falls.257,258
For physically inactive adults, even low-intensity physical activity — such as 15 minutes/day — can yield health benefits.257-259
Before starting an exercise program, a clinical evaluation is recommended. If available, a treadmill stress test while on CV medication can help determine the appropriate exercise intensity based on heart rate. According to the American College of Sports Medicine, light to moderate activity should correspond to 50%-70% of peak heart rate, while moderate to vigorous activity should be in the 70%-85% range for those already adapted.260
6.6. Alcohol Intake
Epidemiological studies suggest that high alcohol consumption is associated with increased risk of stroke, CAD, and HF, while an inverse (log-linear) relationship is observed with MI risk.261 Mendelian randomization studies indicate that the lowest CV risk occurs in abstinent individuals, and that any amount of alcohol may raise blood pressure and BMI.262,263
The upper safety limit for alcohol consumption is approximately 100 g/week, for both men and women.261 Biomarker studies suggest that moderate alcohol intake (especially red wine) may increase HDL-c and adiponectin, decrease fibrinogen,264,265 and improve markers of inflammation and hemostasis.266 On the other hand, high consumption (> 30 g/day) is associated with increased TG and TC. Regarding glucose metabolism, light alcohol intake may reduce the risk of T2DM, showing a U-shaped association in both sexes; however, this association is lost with doses > 50-60 g/day and is independent of the beverage type.267,268
The harmful effects of high alcohol consumption are well documented. Therefore, recommendations should be made with caution since definitive conclusions are still lacking.
6.7. Dietary Supplements and Functional Foods in Dyslipidemia
These options may be considered as an additional strategy for patients who do not achieve lipid targets through lifestyle changes alone. Clinical evidence is variable, and well-designed studies are needed to confirm the efficacy and safety of these supplements.
Main studied functional foods include:
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Soy protein: Believed to reduce cholesterol absorption and increase fecal steroid excretion.269
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Phytosterols: Compete with cholesterol for intestinal absorption. Efficacy depends on dosage, baseline LDL-c levels, and the food carrier used.270 The European Society of Cardiology (ESC)/European Atherosclerosis Society guidelines55 now recommend plant sterols as part of lifestyle changes to reduce cholesterol. However, recent genetic evidence suggests a potential atherogenic effect, reinforcing the need for RCTs with robust CV outcomes before broad recommendations, as noted by the German Cardiac Society.271
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Green tea: May provide vascular benefits by improving endothelial function.272 Proposed mechanisms include reduced intestinal cholesterol absorption228 and increased fecal fatty acid excretion.273
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Sesame seeds: Contain unsaturated fatty acids, vitamin E, and lignans, which may have favorable effects on lipids and CV health by reducing TG levels.274
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Probiotics: May lower TC and LDL-c, improve BMI, and decrease inflammatory markers. The main proposed mechanism is decreased enterohepatic circulation of bile salts.275 Studies report reductions of TC (–13.6%), LDL-c (–8.4%), LDL-c/HDL-c ratio (–12.8%), TG (–9.0%), and oxidized LDL (–11.3%), along with HDL-c increase (+5.5%) with Lactobacillus plantarum.276
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Red yeast rice (RYR): A fermented product synthesized by Monascus purpureus yeast, contains monacolins — bioactive compounds with lipid-lowering effects.277 Monacolin K, similar to lovastatin, is widely used to manage cholesterol. Studies indicate that RYR has varying phytochemical composition and potential synergistic effects, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase more effectively than lovastatin alone. It also shows lower cellular toxicity, especially in muscle cells. However, further research is needed to validate its clinical efficacy.278
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Fish oil: Rich in marine omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), fish oil is recommended in clinical guidelines for patients with HTG.279 It lowers the levels of TG by inhibiting TG synthesis and turnover.280 The results of specific studies on omega-3 treatment will be addressed in the dedicated treatment chapter.
7. Pharmacological Treatment
The treatment of dyslipidemias has undergone remarkable advancements in recent decades. Although lipid-related risk factors for CVD are partly influenced by lifestyle, optimal lipid control often requires additional pharmacological interventions. Statins have traditionally been the cornerstone of treatment, with proven efficacy in lowering LDL-c levels and preventing CV events. When combined with other oral medications, such as ezetimibe and more recently adenosine triphosphate (ATP) citrate synthase inhibitor, these therapies have provided additional improvements in lipid profiles.
However, biotechnological advances have enabled the development of long-acting injectable therapies, such as PCSK9 inhibitors and RNA interference agents, which allow for even greater reductions in LDL-c, with convenient dosing schedules and good tolerability. In parallel, new therapies have emerged targeting specific pathways, including apolipoprotein C-III (ApoC-III), angiopoietin-like proteins 3 and 4, and Lp(a), expanding therapeutic options beyond the control of LDL-c.
More recently, gene therapy and genetic editing approaches have begun to emerge as a new frontier in the management of dyslipidemias, with the potential to permanently modify metabolic pathways involved in lipid regulation. These advancements reflect a paradigm shift in the treatment of dyslipidemia, enabling increasingly personalized and effective interventions for the prevention of ASCVD.
Figure 7.1 illustrates the key molecular targets for therapeutic interventions in dyslipidemia.
Molecular targets of the main treatments for dyslipidemia. BPA: bempedoic acid; CE: cholesteryl esters; LPL: lipoprotein lipase; TG: triglycerides.
7.1 Statins
The decrease in the levels of LDL-c through statin therapy remains the most validated approach for decreasing CV events and overall mortality, both in primary and secondary prevention.55 Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Inhibiting HMG-CoA reductase increases the expression of hepatic LDL receptors, enhancing LDL clearance from circulation. Similarly, the action of statins can potentially affect the broader range of circulating lipoproteins that interact with LDL receptors, such as LDL, VLDL, and chylomicron remnants.
The degree of LDL-c decrease depends on the dose and varies among different statins. High-intensity therapy involves potent statins used at higher doses and typically lowers LDL-c by 50% or more. Moderate-intensity therapy is defined by an expected LDL-c reduction of 30%-50%.37 Importantly, there is considerable interindividual variability in LDL-c decrease with the same dose. Poor responses to statin therapy may be explained by genetic variability but can also result from poor adherence.
Meta-analyses of RCTs have shown that for every 39 mg/dL decrease in LDL-c, statins reduce all-cause mortality by 10% and confer a RR reduction of approximately 22% in CV events (eg, ACS, coronary death, need for myocardial revascularization, or stroke).281
Moreover, more potent statins lead to approximately 15% greater reductions in CV events compared to less intensive regimens.
Statins are therefore recommended as the first-line therapy for reducing CV risk in patients with dyslipidemia.
A lipid profile should be repeated approximately 4 weeks after starting statin therapy or after adjusting the dose. Once lipid targets are achieved, annual testing is generally sufficient unless there are suspected nonadherence or adverse effects.
Side effects are uncommon. Muscle-related symptoms are the most frequent. A recent meta-analysis of over 180 observational studies and RCTs found that the prevalence of statin-induced myopathy is 9%.282 These symptoms usually occur within the first few weeks of treatment but may appear even years later. In most cases, they resolve within a few days of statin discontinuation. Symptoms range from myalgia, with or without creatine kinase (CK) elevation, to rhabdomyolysis. However, the risk of severe muscle injury is < 0.1%. CK should be assessed prior to initiating statin therapy, but routine monitoring is not recommended unless muscle symptoms arise (eg, pain, tenderness, stiffness, cramps, weakness, or localized/generalized fatigue) or there is concomitant use of interacting drugs.
Statins can generally be used in individuals with mild to moderate liver disease, as the risk of severe hepatotoxicity is very low. Baseline assessment of liver enzymes — particularly alanine aminotransferase (ALT) — is recommended before initiating therapy. Routine monitoring is unnecessary unless there are signs or symptoms suggestive of liver injury (eg, fatigue or weakness, appetite loss, abdominal pain, dark urine, or jaundice). Mild ALT elevations (up to 3× ULN [upper limit of normal]) occur in 0.5%-2.0% of statin users, more commonly with potent agents or higher doses. In such cases, therapy should not be discontinued, but liver enzymes should be reassessed in 4-6 weeks. On the other hand, if the levels of ALT rise to more than 3× ULN on two consecutive occasions, statin discontinuation or dose reduction is advised.
An increase in blood glucose and a higher risk of developing T2DM have been observed with statin use. A minor, clinically insignificant rise in HbA1c may also occur. This risk is greater with potent statins, higher doses, older age, and predisposing factors such as overweight or insulin resistance. It is estimated that 255 individuals would need to be treated with statins over 4 years for one additional case of diabetes to occur. Therefore, the absolute reduction in CV risk among high-risk patients clearly outweighs the potential adverse effect of a slight increase in diabetes incidence.283
7.2 Ezetimibe
Ezetimibe is a selective inhibitor of the NPC1L1 protein, which is responsible for intestinal cholesterol absorption. When combined with statins, it provides an additional LDL-c decrease by counteracting the compensatory increase in intestinal cholesterol absorption that occurs following inhibition of hepatic synthesis.
A RCT demonstrated that adding ezetimibe to simvastatin in patients with ACS decreased CV events.165 A total of 18,144 patients with ACS were randomized to receive either simvastatin alone or in combination with ezetimibe and were followed for a median of 6 years. The combination led to a significant reduction in major CV events (HR, 0.936; 95% CI, 0.89-0.99; p = 0.016), proportional to the additional LDL-c decrease (about 17 mg/dL). The benefit was more pronounced in high-risk subgroups, such as patients with diabetes and older individuals.284 In addition, ezetimibe is an effective, safe, low-cost alternative for patients with partial or complete statin intolerance. It is preferred over PCSK9 inhibitors in many clinical scenarios, particularly due to cost and adherence considerations.
The combination of a low dose of a potent statin (rosuvastatin 10 mg) with ezetimibe was shown to be noninferior to high-dose monotherapy with rosuvastatin 20 mg in reducing CV events in the RACING (RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy Versus Statin/Ezetimibe Combination for High-risk Cardiovascular Diseases) trial. Furthermore, the combination was associated with a lower discontinuation rate.191 Studies support the good tolerability of combining ezetimibe with rosuvastatin.285
7.3 Novel Messenger RNA-Targeting Therapies
An innovative therapeutic modality targeting messenger RNA (mRNA) to reduce protein synthesis is already being used to suppress hepatic PCSK9 production and is currently being tested in clinical trials for other types of dyslipidemia, such as TG-rich lipoproteins and Lp(a) decrease. Compared to traditional therapies, mRNA-based treatments offer advantages such as specific inhibition of the target protein and long dosing intervals — up to 6 months. The two main drug classes that reduce protein production by targeting mRNA are:
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Single-stranded ASOs;
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Double-stranded siRNAs.
Both drug classes are administered parenterally, with cytoplasmic release into the target tissue and specific binding to a sequence within the target mRNA. This binding leads to degradation of the target mRNA, resulting in decreased translation of the encoded protein.
7.4 Anti-Proprotein Convertase Subtilisin/Kexin Type 9 Therapy
PCSK9 inhibitors were the first drug class capable of drastically reducing LDL-c levels in patients already using statins. The primary function of the PCSK9 protein is to degrade LDL receptors in hepatocytes. When PCSK9 is inhibited, intact LDL receptors return to the cell surface, allowing for greater LDL particle uptake from the circulation and consequently lowering the levels of LDL-c.
Among PCSK9 inhibitors, the monoclonal antibodies evolocumab and alirocumab — administered subcutaneously every 2-4 weeks — reduce LDL-c levels by approximately 55%-60% in statin users.168,169 In two clinical trials involving patients with ASCVD already on statins, evolocumab and alirocumab reduced the rate of major CV events by 15%, with more pronounced benefits observed after the first year of treatment.168,169 Patients who achieved extremely low LDL-c levels experienced even greater CV benefits.198,286 No significant side effects or cognitive changes were identified over up to 8.4 years of follow-up, even in individuals with levels of LDL-c < 25 mg/dL.203,286,287
Despite these results, lipid-lowering therapies remain underused, highlighting the need for alternative strategies to improve adherence. In this context, inclisiran — a siRNA that inhibits the production of PCSK9 — offers improved dosing convenience, as it is administered subcutaneously every 6 months in a health care setting. Inclisiran provides a substantial and sustained LDL-c reduction of approximately 50%-55% in statin users, without significant side effects.288 Ongoing studies aim to determine whether inclisiran use leads to CV risk reduction in patients with established ASCVD.
Although CV outcome trials for inclisiran are not yet published, its efficacy in sustainably reducing LDL-c supports its inclusion among anti-PCSK9 therapies. Because of the well-established causal relationship between LDL-c levels and CV risk, this drug class is considered a valid option for managing high-risk patients. Nevertheless, differences in the level of supporting evidence should be acknowledged.
Despite the proven efficacy and safety of anti-PCSK9 therapies, their high cost may limit widespread use, especially in Brazil. Therefore, it is suggested to prioritize PCSK9 inhibitor therapy in patients at high risk of ASCVD events or in those who are statin-intolerant.
7.5 Bempedoic Acid
BPA is a lipid-lowering agent used in the treatment of hypercholesterolemia, especially in patients who are statin-intolerant or require adjunctive therapies to achieve desired lipid goals.289,290 It is the first oral drug in the class of hepatic ACLY inhibitors.291 This agent stands out for its ability to inhibit cholesterol biosynthesis, acting similarly to statins but at an earlier metabolic step. By interfering earlier in the cholesterol synthesis pathway, BPA effectively decreases the levels of LDL-c. This reduction is achieved through upregulation of LDL receptor expression, a consequence of decreased intracellular cholesterol concentration.
One of the main advantages of BPA is its suitability for patients who are intolerant or inadequately responsive to statins, offering a viable and effective alternative for managing hypercholesterolemia.292 Furthermore, its action at a distinct metabolic step may enhance the efficacy of combination therapies, providing broader control of lipid levels. These features make BPA a valuable component in dyslipidemia management strategies, particularly in cases requiring additional interventions to reach target levels.
The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial evaluated the efficacy of BPA in reducing CV risk in statin-intolerant patients.293 That double-blind, placebo-controlled RCT included 13,970 patients who were unable or unwilling to take statins due to unacceptable adverse effects. Patients were assigned to receive BPA 180 mg daily or placebo. After a median follow-up of 40.6 months, BPA significantly decreased the levels of LDL-c compared to placebo, with a mean difference of 29.2 mg/dL. Moreover, the incidence of major adverse CV events was significantly lower in the BPA group compared to placebo (11.7% vs. 13.3%; HR, 0.87; 95% CI, 0.79-0.96; p = 0.004). The clinical benefit was proportional to the LDL-c decrease, mirroring findings from statin trials.
7.6 Cholesteryl Ester Transfer Protein Inhibitors and High-Density Lipoprotein Cholesterol–Raising Therapies
RCTs aimed at raising HDL-c levels have yielded predominantly neutral results. Cholesteryl ester transfer protein (CETP) inhibitors significantly increased HDL-c but failed to reduce CV events beyond what would be expected from the accompanying LDL-c decrease.209-212 Similarly, niacin raised HDL-c levels but did not lower CV event rates.213,214 More recently, obicetrapib, a next-generation, oral, low-dose, once-daily CETP inhibitor in development for the treatment of dyslipidemia, cardiovascular risk reduction, and Alzheimer's disease, has been reversing the tide of largely negative results for CETP inhibition and is on track to become the first CETP inhibitor available for clinical use. Unlike earlier compounds in this class, it has demonstrated significant reductions in LDL-c, non-HDL-c, ApoB, Lp(a), and small LDL particles, in addition to increases in functional HDL (pre-β HDL, ApoA-1, ApoE). In the BROADWAY phase 3 trial, in patients with ASCVD or HeFH on maximally tolerated lipid-lowering therapy, it reduced LDL-c by approximately 30%.294 The BROOKLYN phase 3 trial showed LDL-C reductions of 36–41% in HeFH, with more than 50% of patients achieving LDL-c <70 mg/Dl.295 The ongoing PREVAIL phase 3 trial is evaluating the impact on major cardiovascular outcomes in over 9,500 patients with ASCVD and uncontrolled LDL-c.
More recently, an intervention designed to improve HDL function — rather than simply increase HDL-c concentrations — also failed to demonstrate CV benefit.296 There is currently no evidence that raising HDL-c reduces CV event rates.
7.7 Fibrates
Fibrates activate peroxisome proliferator–activated receptor alpha (PPAR-α), which increases the production and activity of LPL — the enzyme responsible for intravascular hydrolysis of TG — and reduces ApoC-III, which normally inhibits LPL. Fibrate therapy also increases the synthesis of ApoA-I, leading to higher HDL concentrations. The levels of TG are typically reduced by 30%-60% with the use of fibrates.
Although two early trials conducted prior to widespread statin use — the Helsinki Heart Study297 and the VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) trial298 — have demonstrated significant reductions in CV risk with gemfibrozil, similar benefits were not observed with fenofibrate in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes)299 and ACCORD (Action to Control Cardiovascular Risk in Diabetes)300 trials or with bezafibrate in the BIP (Bezafibrate Infarction Prevention) trial.301 The ACCORD trial evaluated fenofibrate versus placebo in a population of patients with dyslipidemia and diabetes already on simvastatin therapy and found no significant reduction in fatal CV events, MI, or stroke.300 However, a subgroup analysis of 941 patients with HTG (TG ≥ 204 mg/dL) and low HDL-c (< 35 mg/dL) showed a reduction in CV events among those receiving fibrates. Other studies have also shown benefits in this specific subgroup with high TG and low HDL-c. Nevertheless, an RCT targeting this population was needed.
The PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes) trial assessed the use of pemafibrate — a more potent fibrate for reducing TG and increasing HDL-c — for the prevention of CV outcomes in over 10,000 patients with diabetes, TG levels between 200-499 mg/dL, and HDL-c ≤ 40 mg/dL. More than 95% of patients were on statin therapy, most receiving high-intensity treatment. Despite improvements in TG and other lipoproteins, pemafibrate did not significantly reduce CV events compared to placebo.302 Therefore, despite findings from post hoc or secondary analyses of previous fibrate trials, the PROMINENT trial clearly demonstrated that fibrates are not formally indicated for reducing CV risk in patients at high risk already receiving statins.
On the other hand, fibrates remain first-line treatment for patients with TG ≥ 500 mg/dL, with the primary goal of reducing the risk of acute pancreatitis. In this population, TG decreases with fibrates may be substantial, and treatment should be initiated even in the absence of robust CV benefit. Fenofibrate is preferred when used in combination with statins due to its lower risk of myopathy. The combination with gemfibrozil is contraindicated because of the high incidence of severe muscle-related adverse effects such as rhabdomyolysis.303
7.8 Omega-3 Fatty Acids
Omega-3 fatty acids, particularly EPA and DHA, have been extensively studied for their ability to lower blood levels of TG. However, the clinical benefits of these fatty acids vary depending on the population studied, the dosage used, and the specific formulation administered.
The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) trial demonstrated that icosapent ethyl (IPE), a purified form of EPA, significantly reduced major CV events in patients with established CVD or T2DM who were on statin therapy and had fasting TG levels between 135 and 499 mg/dL.304 In that study, the decrease in CV risk was disproportionate to the TG lowering, suggesting an alternative mechanism of benefit. The 4 g/day IPE formulation used in the trial is not available in Brazil.
In contrast, the STRENGTH (STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia) trial, which evaluated a combination of EPA and DHA in patients at high CV risk, did not show a significant reduction in CV events.305 This discrepancy has sparked debate over differences between purified versus mixed formulations. Other trials using generic EPA/DHA supplements have shown inconsistent results regarding CV outcomes, despite effectively lowering TG levels.306-310
For patients with TG ≥ 500 mg/dL — who were not included in the REDUCE-IT trial — omega-3 therapy is primarily supported for reducing the risk of pancreatitis. Previous studies have shown that daily doses of 2 to 4 g of EPA plus DHA can reduce TG levels by up to 45% in this population. Although the direct CV benefits remain unclear in this group, guidelines from the American Heart Association and the Endocrine Society recommend omega-3s as part of a comprehensive strategy for lipid-lowering and metabolic complication prevention.311,312
Overall, omega-3s have a favorable safety profile, with adverse effects generally mild, including gastrointestinal discomfort and a fishy aftertaste. However, they may exert antiplatelet effects, requiring caution when combined with other antithrombotic therapies, and have been associated with an increased risk of atrial fibrillation.
7.9 Apolipoprotein C-III Inhibitors
ApoC-III is a glycoprotein that plays a key role in the regulation of TG levels. ApoC-III inhibits the activity of LPL, the enzyme responsible for TG hydrolysis, and reduces hepatic clearance of TG-rich lipoproteins, resulting in increased serum TD levels. Loss-of-function variants in the gene encoding ApoC-III have been associated with decreased TG levels and lower CV risk.313,314
Volanesorsen, an ASO, acts on mRNA to prevent ApoC-III protein synthesis, thereby lowering TG levels. In patients with TG ≥ 500 mg/dL of various etiologies, volanesorsen reduced the risk of pancreatitis by 82% and yielded a relative reduction in hepatic steatosis of 24%-53%.315,316 Despite these promising results, thrombocytopenia emerged as a frequent adverse event.317 Currently, the drug is approved in Brazil for adults with FCS, a condition characterized by mutations in genes related to LPL.
More recently, olezarsen, a next-generation ASO, also demonstrated efficacy in patients with FCS, reducing TG levels by up to 44% compared to placebo and lowering the risk of pancreatitis by 88%318 In patients with predominantly moderate HTG, olezarsen decreased TG levels by 49%-53% compared to placebo.319
Plozasiran, a siRNA that blocks the synthesis of ApoC-III, lowered TG levels by up to 62% versus placebo in patients with moderate to severe HTG and reduced the risk of pancreatitis by 83% in patients with chylomicronemia.320-322 In early trials, adverse events associated with olezarsen or plozasiran were uncommon and included mild injection site reactions, slight transaminase elevation, and — in the case of plozasiran — hyperglycemia. Thrombocytopenia was not reported as a treatment-related adverse event. Both agents are still under investigation and not yet approved for use in Brazil.
7.10 Angiopoietin-Like Protein 3 Inhibitors
Angiopoietin-like protein 3 (ANGPTL3) is an endogenous inhibitor of LPL. Members of the ANGPTL protein family are recognized as important regulators of lipoprotein metabolism and have been investigated as pharmacological targets for the reduction of ASCVD risk. Loss-of-function mutations in ANGPTL3 are associated with reduced risk of CAD, while gain-of-function mutations are linked to increased CAD risk.323 ANGPTL3 deficiency leads to reductions in TG, LDL-c, and HDL-c. Importantly, LDL-c reduction occurs independently of the LDL receptor.
Evinacumab is a monoclonal antibody that inhibits ANGPTL3 to reduce the concentration of TG-rich remnant lipoproteins with atherogenic potential. Because it does not rely on LDL receptor function, evinacumab can be used as adjunctive therapy for decreasing LDL-c in patients with HoFH324,325 — a rare genetic condition marked by extremely high levels of LDL-c from childhood and a markedly increased risk of premature CVD. Accordingly, evinacumab is approved for use in adults and pediatric patients aged 5 years and older with HoFH who do not achieve LDL-c targets despite maximally tolerated lipid-lowering therapy. The recommended dose is 15 mg per kilogram of body weight, administered via intravenous infusion over 60 minutes every four weeks. The most common side effects include flu-like symptoms (eg, fever and headache), infusion-site reactions, and gastrointestinal complaints.
A recent trial of an ANGPTL3-targeting ASO was halted due to increased liver enzymes and hepatic fat accumulation.326 Three additional studies investigating siRNA therapies are currently ongoing.
7.11 Lipoprotein(a) Inhibitors
Apo(a) is a component of Lp(a), which has been associated with MI, stroke, and aortic valve stenosis. Currently, no specific treatment is available to decrease the levels of Lp(a). New therapies offer hope for patients with significantly elevated Lp(a) — a subgroup for whom no targeted treatments currently exist. The main strategies under development are RNA-silencing therapies, especially ASOs and siRNAs, designed to decrease hepatic production of Apo(a).
7.12 Clustered Regularly Interspaced Short Palindromic Repeats and Gene Therapies
Gene-editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 are being explored as potential "genetic cures" for hereditary dyslipidemias. In animal models, a single CRISPR-based edit targeting the PCSK9 gene resulted in sustained LDL-c decreases (> 60%) for over 1 year. Although still experimental, this approach could revolutionize the treatment of lipid disorders.
7.13 Combination Therapy
The standard approach to achieving LDL-c targets typically involves a stepwise strategy with lipid-lowering therapies: treatment begins with a statin — usually a high-intensity statin at the highest recommended or tolerated dose — followed by sequential addition of ezetimibe and if necessary PCSK9 inhibitors. However, there remains a significant gap between guideline recommendations and clinical practice, with registry data showing low rates of LDL-c control, therapeutic inertia, and poor adherence to treatment.25,327 In response to this challenge, the treatment paradigm has shifted from the concept of high-intensity statins to that of high-intensity lipid-lowering therapy, emphasizing combination therapy from the outset.328,329 This approach aims to reduce CV risk more rapidly and effectively, particularly in individuals at very high CV risk.
Studies have shown that the efficacy in lowering LDL-c can be significantly enhanced through the use of combination lipid-lowering therapies:
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High-intensity statin + ezetimibe: LDL-c reduction of up to 65%, representing a widely recommended strategy for high-risk patients.
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High-intensity statin + ezetimibe + PCSK9 inhibitor: LDL-c reductions exceeding 85%, currently the most potent regimen available.
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Moderate-intensity statin + ezetimibe: When high-intensity statins are not tolerated, the combination of a moderate-intensity statin with ezetimibe may achieve an additional 20–25% reduction.
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Moderate-intensity statin + bempedoic acid + ezetimibe: An effective alternative for patients intolerant to high-intensity statins, with LDL-c reductions of up to 60%.
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Bempedoic acid + ezetimibe + PCSK9 inhibitor: A non-statin strategy that may achieve LDL-c reductions greater than 75%, particularly useful in cases of statin intolerance or contraindication.
Other therapeutic combinations are also possible, as illustrated in Figure 7.2, which presents various lipid-lowering regimens tailored to clinical needs and patient tolerance profiles.
Efficacy of lipid-lowering therapy in LDL-c reduction.78 MIS: moderate-intensity statin; HIS: high-intensity statin; EZE: ezetimibe; BA: bempedoic acid; anti-PCSK9: anti-proprotein convertase subtilisin/kexin type 9 therapy. *Approximate values.
These combinations reflect the concept of high-intensity lipid-lowering therapy, which emphasizes synergistic pharmacologic interventions from the outset, aiming to overcome clinical barriers and optimize lipid control in high-risk populations.
7.13.1 Benefits of Combination Therapy
Registry data show that most patients still fail to achieve recommended LDL-c targets despite the availability of a broad range of therapeutic options.25,27,28,327,330 In the REACT study, which included 2,364 patients at high CV risk in Brazil, 77% were on statins, yet 20%-30% had LDL-c levels ≥ 100 mg/dL.331
7.13.2. Statin and Ezetimibe Combination
The IMPROVE-IT trial showed that adding ezetimibe 10 mg to simvastatin 40 mg resulted in an additional 24% reduction in LDL-c levels and a proportional 7.2% reduction in major CV events compared to statin monotherapy over 7 years. On average, high-intensity statin monotherapy reduces LDL-c by approximately 50%; when combined with ezetimibe, this reduction increases to about 65%.332
A simulation analysis of the DA VINCI study, which included 2,482 patients who had not reached LDL-c goals, showed that statin monotherapy optimization would not be sufficient for most patients to achieve targets. However, the addition of ezetimibe would double the proportion of individuals reaching their LDL-c targets, regardless of their CV risk category.333
Supporting this evidence, the RACING trial demonstrated that combining rosuvastatin 10 mg with ezetimibe was noninferior to rosuvastatin 20 mg monotherapy in reducing major CV outcomes. Among these two high-intensity lipid-lowering strategies — one using a moderate-intensity statin plus ezetimibe and the other using high-intensity statin monotherapy — the combination approach led to greater LDL-c goal achievement over time and lower treatment discontinuation rates.191
7.13.3 Statin and Proprotein Convertase Subtilisin/Kexin Type 9-Targeted Therapy Combination
In the FOURIER trial, evolocumab, a PCSK9-targeted agent, reduced LDL-c by 59% and the risk of major CV events by 15% over a 26-month follow-up in patients already receiving optimized statin doses.168 In the ODYSSEY OUTCOMES trial, alirocumab decreased LDL-c by up to 62.7% and major CV events by 15% in patients receiving high-intensity statin therapy.169
More recently, an implementation strategy using inclisiran — administered immediately after failure to achieve LDL-c < 70 mg/dL despite maximally tolerated statin therapy — showed superior effectiveness compared to usual care: 81.8% of patients reached LDL-c < 70 mg/dL and 71.6% achieved LDL-c < 55 mg/dL, compared to 22.2% and 8.9%, respectively, in the usual care group.3334
7.13.4. Ezetimibe and Bempedoic Acid Combination
In a phase 3 randomized controlled trial (RCT) involving patients at high CV risk (about 65% previously on statins), the combination of ezetimibe and bempedoic acid reduced LDL-c levels by 38%, compared to reductions of 17% with bempedoic acid alone and 23% with ezetimibe alone.335
7.13.5. Statin, Ezetimibe, and Proprotein Convertase Subtilisin/Kexin Type 9-Targeted Therapy Combination
The combined use of high-intensity statins, ezetimibe, and PCSK9-targeted therapy can lead to an approximate 85% reduction in LDL-c levels. This strategy may be particularly suitable for patients at very high or extreme risk, or for those with severe hypercholesterolemia who fail to reach LDL-c goals with dual therapy.
7.13.6. Statin, Ezetimibe, and Bempedoic Acid Combination
In a simulation analysis involving 105,577 patients at high (n = 28,677) or very high (n = 76,900) CV risk, 88% were on statin monotherapy. The sequential addition of ezetimibe and BPA significantly increased LDL-c target attainment rates: from 11.2% with statin alone to 33.1% with statin plus ezetimibe, and to 61.9% with the further addition of BPA.336
8. Management of Statin Intolerance
Statin intolerance typically presents as muscle-related complaints, which may include pain, weakness, or cramps. This issue is clinically relevant due to the association between nonadherence or discontinuation of statin therapy and an increased risk of CVD.
8.1 Definition
Statin intolerance is defined as the inability to tolerate various statins, at any dose, due to the onset of symptoms and/or laboratory abnormalities, requiring treatment discontinuation. Symptoms and/or laboratory abnormalities must resolve upon statin withdrawal and recur upon rechallenge with the same or another statin. These effects should not be attributable to drug interactions or to conditions known to increase the likelihood of statin intolerance.
8.2 Prevalence
According to a meta-analysis,282 the prevalence of statin intolerance is significantly lower in RCTs than in cohort studies (4%-21%). Higher prevalence rates have been observed in populations under primary prevention compared to secondary prevention, and among older individuals, women, Asians, and Black individuals as well as in those with obesity, diabetes, hypothyroidism, liver disease, renal dysfunction, concomitant use of antiarrhythmic drugs or calcium channel blockers, and with increasing statin doses.282 The conclusion of this analysis, which included over 4 million patients, suggests that the prevalence of statin intolerance is frequently overestimated and highlights the need for careful evaluation of patients with suspected statin-related symptoms.282
8.3 Diagnosis
Several diagnostic criteria for statin intolerance have been proposed; however, they all rely on clinical judgment and laboratory tests.337 To date, no sensitive or specific biomarkers have been identified. Therefore, diagnosis requires the exclusion of other possible causes and a clear causal relationship between statin use and adverse effects.337 In cases of suspected intolerance, four key elements must be identified:337
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Clinical presentation: includes subjective symptoms such as myalgia, muscle weakness, or cramps, and/or abnormal lab findings (CK, AST, or ALT);
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Type and dose of statin: patients must be unable to tolerate at least two different statins, one of which at the lowest daily dose (eg, atorvastatin 10 mg, rosuvastatin 5 mg, simvastatin 5 mg, pitavastatin 1 mg, pravastatin 10 mg, fluvastatin 20 mg, lovastatin 20 mg);
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Timing and causality: adverse reactions must occur after statin initiation or dose escalation, improve upon discontinuation, and reappear upon rechallenge;
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Exclusion of other causes: the likelihood that adverse reactions are due to other diseases or drug interactions must be low.
8.4 Nocebo Effect
The nocebo effect refers to the manifestation of adverse symptoms that are not pharmacologically attributable to treatment but rather arise from negative patient expectations. In the context of statins, this effect can lead to premature treatment discontinuation. The etiology of the nocebo effect is linked to the anticipation of harm triggered by various factors, such as the prescriber's communication about potential side effects, detailed informed consent procedures in clinical trials, exposure to nonclinical information sources (eg, the internet or social media), and observing symptoms in other patients.338
8.5 Muscle Symptoms
The term statin-associated muscle symptoms (SAMS) is commonly used to refer to muscle-related symptoms linked to statin use, such as pain, cramps, or weakness. However, this terminology does not necessarily imply a causal relationship with statin therapy. Muscle symptoms are typically bilateral, symmetrical, and limited to skeletal muscles.339
8.5.1. Clinical Characteristics, Classification, and Management of Statin-Associated Muscle Symptoms
The clinical management of SAMS should be guided by both the presence of muscle symptoms and CK elevation, following the seven patterns of SAMS outlined in the current guideline. These patterns range from asymptomatic CK elevation up to 3× ULN (SAMS 0), to tolerable (SAMS 1) and intolerable myalgia (SAMS 2), moderate (SAMS 3) and severe myopathy (SAMS 4), rhabdomyolysis (SAMS 5), and immune-mediated necrotizing myositis (SAMS 6). Recognizing the distinct phenotypes and severity levels helps facilitate practical clinical management (Figures 8.1 and 8.2).
Flowchart for the investigation and probable diagnosis of SAMS. ANA: antinuclear antibodies; BPA: bempedoic acid; CK: creatine kinase; ESR: erythrocyte sedimentation rate; HDL-c: LDL-c: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9; ULN: upper limit of normal; T4: thyroxine; TSH: thyroid-stimulating hormone.
Flowchart for the specific diagnosis and management of SAMS. ANA: antinuclear antibodies; CK: creatine kinase; ESR: erythrocyte sedimentation rate; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; LDL-c: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9; SAMS: statin-associated muscle symptoms; T4: thyroxine; TSH: thyroid-stimulating hormone; ULN: upper limit of normal..
When assessing a potential SAMS case, it is important to (i) acknowledge all muscle complaints (pain, weakness, or cramps), not just pain, and to consider previous muscle symptoms, comorbidities, and concomitant medications; (ii) recognize the usual time frame between statin initiation and symptom onset, typically 4 to 12 weeks, though symptoms may rarely occur after more than a year or emerge abruptly after dose escalation or the introduction of a drug or food that affects pharmacokinetics;340 (iii) understand that the pattern of muscle pain and weakness is usually symmetrical and proximal, affecting large muscle groups such as the gluteal muscles, thighs, calves, and dorsal musculature. Muscle complaints are more frequent in physically active individuals.
In the presence of intolerable muscle pain, serum CK levels should be measured immediately. If CK levels exceed 7× ULN or remain persistently above 3× ULN, thyroid function (TSH, free T4), erythrocyte sedimentation rate (ESR), and antinuclear factor (ANF) should also be assessed. In cases of intolerable symptoms, serum urea, creatinine, and myoglobinuria should also be tested. If a secondary cause that could explain SAMS is identified, it should be addressed, and the statin should be reintroduced at a low dose with gradual titration.
8.5.2. Tolerable and Intolerable Muscle Symptoms
Most often, muscle complaints occur without substantial CK elevation.341 The most important step in such cases is to determine symptom tolerability, as the impact can vary widely among individuals, especially in those with comorbidities such as hypothyroidism, collagen diseases, and fibromyalgia.
In cases of tolerable muscle pain with or without CK elevation (SAMS 0) or with elevation up to 3× AND 7x ULN (SAMS 1), temporary dose reduction or statin switching may be considered, but no additional concern is warranted (Figure 8.1). If CK levels are elevated between 3× and 7× ULN with tolerable symptoms, dose reduction and closer CK monitoring are required (Figure 8.2). In the presence of intolerable symptoms and CK elevation (SAMS 2), statin discontinuation becomes necessary and should prompt a broader diagnostic investigation (Figures 8.1 and 8.2). Newly occurring muscle complaints meeting the clinical suspicion for SAMS should therefore trigger a CK test request. Overall, the less severe forms of SAMS (SAMS 0 to 4) are self-limiting and do not result in permanent damage.
8.5.3. Creatine Kinase Elevation
During statin therapy, transient elevations in CK may occur even in asymptomatic patients, but they are generally not clinically significant. Thus, routine CK monitoring during statin therapy is not recommended, except when a new medication is introduced or the statin dose is increased. Among patients requiring new CK testing, those who are asymptomatic with mild CK elevations (< 3× ULN) (SAMS 0) do not need to discontinue or adjust their statin regimen (see Flowcharts 1 and 2). In asymptomatic patients with CK elevations between 3× and 7× ULN (SAMS 1), treatment interruption is not required; the same or a different statin may be reinitiated at a low dose, with dose titration every 4-6 weeks.
Similarly, the current Brazilian Society of Cardiology (SBC) guideline recommends temporary discontinuation of statin therapy and periodic CK monitoring every 4-6 weeks if CK levels are between 3× and 7× ULN in the presence of intolerable muscle symptoms (SAMS 2). For those with CK levels between 3 and 7× ULN and tolerable or no symptoms (SAMS 1), switching to a low-intensity statin regimen and closer CK monitoring every 4–6 weeks is recommended.
However, regardless of the presence of symptoms, if CK levels exceed 7× ULN, statin therapy should be discontinued for 4-6 weeks, followed by repeat CK measurement and reassessment. If CK does not decrease < 7× ULN within 6 weeks off statin therapy (SAMS 4 or SAMS 6), the patient should be evaluated for secondary causes through detailed clinical and laboratory investigations, including assessment of renal function, thyroid hormones (TSH, free T4), erythrocyte sedimentation rate (ESR), and antinuclear factor (ANF). If no pain improvement occurs after statin discontinuation and no associated causes are found, differential diagnosis between immune-mediated myopathy (SAMS 6) and non-statin-related myopathy should be considered.
In cases where serum CK levels decrease after discontinuation but rise again to > 7x ULN during statin reintroduction or dose titration (after excluding secondary causes such as exercise, hypothyroidism, or metabolic myopathies), a lower dose of the same statin or an alternative statin should be used. Subsequently, non-statin lipid-lowering therapy should be added to achieve the lowest possible level of LDL-c relative to the target goal.
8.5.4. Rhabdomyolysis
Rhabdomyolysis (SAMS 5) is the most severe muscle-related adverse event associated with statin therapy. It may lead to muscle necrosis, serious electrolyte disturbances, acute kidney injury, coagulopathy, shock, and death. The most observed diagnostic criterion is muscle pain accompanied by a sudden increase in CK levels > 10× ULN. However, in rarer cases, rhabdomyolysis may present as muscle weakness or mild symptoms with CK elevations exceeding 40-50× ULN. Therefore, for diagnostic purposes, rhabdomyolysis is defined as either an asymptomatic CK elevation > 50× ULN or muscle pain with CK > 10× ULN combined with renal dysfunction (defined as a rise in serum creatinine ≥ 0.5 mg/dL) and myoglobinuria.
8.5.5. Statin-Induced Immune-Mediated Necrotizing Myopathy
Statin-associated immune-mediated necrotizing myopathy (SAMS 6) is typically related to the presence of serum autoantibodies directed against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacological target of statins. In most cases of statin-associated myopathy, symptoms resolve after drug discontinuation. However, in exceptionally rare instances, an autoimmune myopathy may develop. On physical examination, patients typically report muscle weakness, such as difficulty rising from a chair, climbing stairs, or lifting heavy objects. Laboratory findings reveal markedly elevated and persistent CK levels (usually > 2,000 U/L) despite statin withdrawal.
Diagnosis is established by detecting anti-HMGCR autoantibodies in the context of prior statin exposure, muscle symptoms, and persistent CK elevation.342,343 Muscle biopsy typically shows myocyte necrosis and inflammatory infiltration.343 Treatment includes corticosteroids and immunosuppressive therapy.343 Unlike other forms of SAMS, symptoms in SAMS 6 do not improve after statin discontinuation. However, since statin exposure is the underlying trigger, immediate discontinuation remains essential.
8.6. Factors Associated with Statin Intolerance
Numerous factors, both pharmacological and patient-related,343 may contribute to the development of statin-associated adverse effects. Some are listed in Table 8.1. Table 8.2 presents key drug interactions that may exacerbate or trigger muscle symptoms in statin users.
8.7. Management of Statin-Intolerant Patients
It is advisable to monitor patients for the development of SAMS, particularly during the first few months of statin therapy and after dose increases. CK levels should be measured if symptoms occur. Patients with known risk factors for SAMS require closer monitoring due to their increased risk of developing rhabdomyolysis.
Statin therapy should be discontinued immediately if CK levels exceed 10x ULN or if myopathy is suspected or diagnosed. In cases of moderate CK elevation (3× to 10× ULN), weekly CK monitoring is recommended. A baseline CK measurement should be obtained before initiating statin therapy, especially in individuals at high risk for muscle-related adverse events, such as those with a history of statin intolerance, a family history of myopathy, or concurrent use of drugs that increase the risk of myopathy. Routine CK testing is not recommended in asymptomatic individuals without medication changes or comorbidities.
Baseline liver enzyme testing (ALT and AST) should be performed before starting statin therapy. During treatment, liver function should be assessed if symptoms or signs suggest hepatotoxicity (eg, fatigue, weakness, loss of appetite, abdominal pain, dark urine, or jaundice). If liver enzyme abnormalities are present, potential contributing factors should be excluded and a possible link to statin use investigated. If ALT/AST levels exceed 3× ULN along with an increase in total bilirubin, statin dose reduction or discontinuation should be considered. If ALT/AST elevations are < 3× ULN, observation or switching to a statin with a different metabolic pathway (eg, pravastatin) is recommended.
A small proportion of patients may experience increases in liver enzymes — particularly ALT and AST — with little or no impact on gamma-glutamyl transferase, alkaline phosphatase, or bilirubin. Statin-induced transaminase elevations typically occur within the first 6 months of treatment, are asymptomatic, and usually resolve with dose reduction or discontinuation. Isolated transaminase elevations, in the absence of elevated bilirubin, have not been clinically or histologically linked to acute or chronic liver injury.344
8.7.1. Discontinuation and Reintroduction of Statin Therapy
Discontinuation of statin therapy in patients at CV risk is associated with an increased incidence of major adverse CV events and mortality.345 Therefore, every effort should be made to encourage patients to remain on treatment. The first step in maintaining therapy is to discontinue the statin (if still in use) and implement a 2-week washout period to assess whether symptoms resolve.
Alongside statin withdrawal, it is advisable to initiate non-statin lipid-lowering therapy — such as ezetimibe, BPA, and/or PCSK9 inhibitors — to mitigate the risks associated with increased levels of LDL-c if statins are discontinued without therapeutic replacement.346,347 Patients should be clearly informed that ezetimibe, BPA, and PCSK9 inhibitors are not part of the statin class, in order to reduce misconceptions that may compromise treatment adherence.348
After this period, reintroduction of the same statin at a lower dose or substitution with a different statin may be attempted.345 Switching to a statin metabolized through an alternative pathway may benefit some patients (eg, replacing the lipophilic, hepatically metabolized atorvastatin with a hydrophilic statin such as rosuvastatin or pravastatin, which are partially renally excreted, or pitavastatin, which is also lipophilic but metabolized via alternative hepatic pathways).
Although not supported by clinical trials, for patients who are highly reluctant to resume daily statin use or who have experienced symptoms with more than two daily statin regimens, intermittent dosing with a long half-life statin (eg, rosuvastatin, atorvastatin, or pitavastatin) may be attempted.
Following statin reinitiation, adjunctive lipid-modifying agents may be used to help achieve target levels of LDL-c. In cases of absolute intolerance to any statin dose, combination or standalone non-statin therapies may be employed (Figures 8.1, 8.2 e 8.3).
Simplified flowchart. ANA: antinuclear antibodies; CK: creatine kinase; ESR: erythrocyte sedimentation rate; PCSK9: proprotein convertase subtilisin/kexin type 9; T4: thyroxine; TSH: thyroid-stimulating hormone; ULN: upper limit of normal.
8.7.2. Use of Products Without Proven Benefit
Vitamin D deficiency has been associated with the occurrence of statin-associated muscle symptoms; however, supplementation has not been shown to improve muscle-related outcomes.349
Coenzyme Q10 (CoQ10) is an essential compound for mitochondrial energy production and functions as an antioxidant. Statin therapy may reduce CoQ10 levels in the body, which has been proposed as a contributing factor to fatigue and muscle pain. This is due to statins inhibiting the HMG-CoA reductase enzyme, which is not only involved in cholesterol synthesis but also in the biosynthesis of CoQ10.350,351 While this biological rationale supports a possible benefit in mitigating SAMS, meta-analyses and larger trials350-353 have not demonstrated any clear efficacy. Before, there is insufficient evidence to recommend CoQ10 supplementation in patients undergoing statin therapy for SAMS.
8.7.3. Drug interactions of statins
8.7.3.1. Anticoagulants
Drug interactions between statins and warfarin have been reported, primarily mediated by CYP2C9 pathway inhibition, especially with fluvastatin and rosuvastatin, or by displacement from protein-binding sites, as seen with lovastatin. Most statins, except for pravastatin, have potential for this interaction.354 In contrast, studies have shown no clinically significant interactions between warfarin and atorvastatin or pitavastatin. Similarly, no relevant interactions have been demonstrated with direct oral anticoagulants (DOACs) such as dabigatran, apixaban, rivaroxaban, and edoxaban.355 For patients on warfarin, intensified monitoring of the international normalized ratio (INR) is mandatory when initiating or adjusting a statin.
8.7.3.2. Azole Antifungals
Azole antifungals act as CYP3A4 isoenzyme inhibitors, which blocks the metabolism of statins processed through this pathway. This interaction increases statin plasma concentrations, raising the risk of myopathy and rhabdomyolysis.356 Coadministration of itraconazole with simvastatin or lovastatin is contraindicated due to a marked increase in statin exposure (up to 20-fold increase in AUC), critically elevating musculoskeletal toxicity risk.357
In contrast, pravastatin, which is not metabolized via CYP3A4, does not have significant interaction with itraconazole.358 When rosuvastatin is combined with fluconazole, an increase in AUC and Cmax is observed, but with no demonstrated clinical relevance. Therefore, for patients on azole antifungals, pravastatin — and to a lesser extent, fluvastatin or rosuvastatin (with monitoring) — represent safer therapeutic alternatives.
8.7.3.3. Antiretroviral Agents
Managing dyslipidemia in HIV-positive patients is increasingly common due to improved survival and increased CV risk. Antiretroviral therapy (ART) poses clinically significant interactions with statins, mainly via CYP3A4 modulation by protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).359
Pravastatin, due to its sulfation metabolism, and pitavastatin are the statins of choice and safest options in this context. However, pravastatin may require dose adjustment (increase) when associated with PIs such as nelfinavir or ritonavir. Conversely, simvastatin and lovastatin should be avoided with PIs. Atorvastatin is also discouraged with potent PIs (eg, ritonavir, atazanavir). Rosuvastatin requires caution, as its combination with lopinavir/ritonavir or atazanavir/ritonavir has been shown to substantially increase systemic exposure (AUC and Cmax). In contrast, efavirenz (an NNRTI) acts as an enzymatic inducer, lowering the concentrations of atorvastatin, simvastatin, and pravastatin, which requires clinical monitoring and potential dose adjustments to maintain lipid-lowering efficacy.360
8.7.2.4. Calcium Channel Blockers
Diltiazem may increase simvastatin's Cmax by 3.6-fold and AUC by 5-fold, and lovastatin's by 3.5-fold, raising the risk of myopathy.361 Dose adjustments are recommended for patients treated with verapamil and simvastatin (maximum 20 mg/day) or lovastatin (maximum 40 mg/day).
The dihydropyridine calcium channel blocker amlodipine also increases simvastatin's Cmax and AUC.362 The U.S. Food and Drug Administration (FDA) recommends that simvastatin doses should not exceed 20 mg/day when coadministered with any dose of amlodipine, due to the elevated risk of myopathy and/or rhabdomyolysis at higher doses.
8.7.3.5. Antiarrhythmic Agents
Amiodarone is an irreversible CYP3A4 inhibitor and may interact with statins metabolized by CYP450 or that are P-gp substrates. Reports have shown increased toxicity when amiodarone is combined with CYP3A4-substrate statins, particularly simvastatin. A 75% increase in both AUC and Cmax of simvastatin has been observed when coadministered with amiodarone.363
No dose adjustments are required for atorvastatin, rosuvastatin, pravastatin, fluvastatin, or pitavastatin when used with amiodarone. However, lovastatin should not exceed 40 mg/day, and simvastatin should be limited to no more than 20 mg/day when prescribed with amiodarone.
8.7.3.6. Immunosuppressants
Coadministration of statins with calcineurin inhibitors (eg, cyclosporine, tacrolimus) and mTOR inhibitors (eg, everolimus, sirolimus) significantly increases the risk of myopathy and rhabdomyolysis. This interaction occurs through inhibition of CYP3A4 and the OATP1B1 transporter, raising serum statin levels. Clinically, it is recommended to avoid combinations with lovastatin, simvastatin, and pitavastatin. When therapy is essential, fluvastatin (up to 40 mg/day), pravastatin (≤ 20 mg/day), or rosuvastatin (≤ 5 mg/day) may be used. Atorvastatin doses > 10 mg/day require strict monitoring of CK levels and symptoms of muscle toxicity.364,365
8.7.3.7. Macrolides
Macrolides — especially clarithromycin and erythromycin — are potent CYP3A4 inhibitors, followed by the weaker inhibitor roxithromycin and, lastly, azithromycin. CYP3A4 is the isoenzyme that metabolizes simvastatin, lovastatin, and atorvastatin, and its inhibition increases plasma statin concentrations and the risk of myotoxicity. Rosuvastatin, fluvastatin, and pravastatin are not significantly affected by this interaction. Among macrolides, azithromycin is considered safe for use with all statins. Erythromycin significantly increases simvastatin and atorvastatin levels.366 Therefore, simvastatin, lovastatin, and atorvastatin should be avoided in combination with erythromycin and clarithromycin due to the increased risk of myopathy.
8.7.3.8 Interactions Between Lipid-Lowering Agents
Although combining statins with fibrates can be effective for lipid lowering, it also increases the risk of myopathy. This interaction is particularly critical with gemfibrozil, which inhibits statin glucuronidation, increasing their serum concentrations. Gemfibrozil should not be combined with lovastatin, pravastatin, or simvastatin.304 Its combination with atorvastatin, pitavastatin, and rosuvastatin may be considered if clinically indicated, despite a modest increase in statin levels. Fluvastatin does not exhibit pharmacokinetic interaction with gemfibrozil and can be used without dose restrictions. In contrast, fenofibrate has a safer profile and its use with any statin is considered acceptable when clinically indicated.
9. Dyslipidemia in Specific Populations: Clinical Management Considerations
9.1 Heart Failure
Dyslipidemia is a common comorbidity in patients with HF, particularly when ASCVD is present. Adequate lipid control is essential, as it can significantly influence clinical outcomes in this population. Statins are recommended for individuals with ischemic HF due to their proven effectiveness in reducing CV events. However, in patients with HF with reduced ejection fraction (HFrEF) without established ASCVD, the mortality benefit of statin therapy remains uncertain.
Importantly, tatin discontinuation in patients with HF — even in those with advanced or decompensated disease — is not recommended. There is no robust evidence to support such a practice, and observational studies suggest increased mortality and hospitalization rates following statin withdrawal, particularly in older patients.367-370
The prevalence of HF, dyslipidemia, and CAD is especially high among older adults. In this population, polypharmacy is a frequent concern and may lead to unintentional discontinuation of statins or other lipid-lowering agents. However, such interruptions may increase the risk of CV events and death, as demonstrated in observational studies.369
For patients who do not reach LDL-c targets with statins — particularly those at high CV risk — additional therapies such as ezetimibe or PCSK9 inhibitors should be considered.
In conclusion, the management of dyslipidemia in HF should be individualized, with an emphasis on maintaining lipid-lowering therapy, especially in patients with ASCVD. Statin discontinuation is not recommended due to the increased risk of adverse events. In older patients, careful assessment of polypharmacy is essential to avoid inappropriate treatment interruption. Further studies are needed to clarify the role of emerging lipid-lowering therapies in this clinical setting.371
9.2 People Living with HIV
People living with HIV (PLWH) have nearly twice the risk of CVD compared to the general population, due to factors such as chronic inflammation, adverse effects of ART, and a high prevalence of traditional risk factors.124 Despite the availability of effective LDL-c-lowering therapies, achieving lipid targets in this population remains a significant challenge. Statins continue to be the cornerstone of LDL-c reduction in PLWH; however, their use is often hindered by drug interactions with ART, leading to increased adverse effects and poor adherence.372 (Table 9.1). The REPRIEVE trial demonstrated a 35% reduction in CV events with pitavastatin use, underscoring its role in primary prevention.372 Nonetheless, challenges such as statin intolerance and underutilization of therapy persist, with studies showing that only 37% of PLWH at high risk receive appropriate lipid-lowering treatment.124
Ezetimibe has also been underutilized, with only 3.3% of patients receiving this therapy despite its favorable safety profile.373 Moreover, traditional CV risk calculators often underestimate risk in PLWH, highlighting the need for individualized approaches that incorporate HIV-specific factors such as immune activation and ART exposure.374 Evolocumab, a PCSK9 inhibitor, has emerged as a promising alternative for PLWH with statin intolerance or residual CV risk. The BEIJERINCK trial demonstrated a 56.9% decrease in the levels of LDL-c, with 72.5% of patients achieving a ≥ 50% decrease.373 Additionally, evolocumab was shown to reduce the levels of Lp(a), which may be particularly relevant in PLWH because of the inflammatory milieu associated with chronic viral infection.373
Achieving LDL-c goals in PLWH remains a relevant clinical challenge, marked by barriers such as drug interactions, poor treatment adherence, and underuse of available therapeutic options. Despite the well-established role of statins as the foundation of lipid-lowering therapy, incorporating new strategies — especially PCSK9 inhibitors — represents a promising approach to improving CV outcomes in this population at high risk. Therapeutic advancement, coupled with personalized care, may contribute substantially to overcoming these limitations and reducing residual risk.375,376
9.3. Diabetes
Diabetes is a metabolic disorder that frequently predisposes individuals to CVD, making it one of the leading causes of morbidity and mortality in patients with T1DM and T2DM. Recent data indicate that diabetes per se increases the risk of CVD by approximately twofold on average; however, this risk varies considerably depending on the population and the preventive strategies adopted.377,378 Individuals with both diabetes and CAD have a significantly higher risk of future CV events. In the case of T2DM, the risk of ASCVD is largely influenced by the presence of target organ damage, such as nephropathy (microalbuminuria), neuropathy, or retinopathy — with the risk increasing as more conditions are present.379
Good glycemic control in T1DM leads to fewer CV events. However, in T2DM, the presence of CVD is independent of intensive glycemic control.380 In addition to insulin resistance and deficiency, dyslipidemia is a common comorbidity in patients with diabetes and can significantly affect clinical outcomes. Increased TG or low fasting and postprandial HDL-c levels are observed in approximately half of individuals with T2DM381 and are also frequently found in those with abdominal adiposity, insulin resistance, or impaired glucose tolerance.382
9.3.1. Specific Characteristics of Dyslipidemia in Insulin Resistance and Type 2 Diabetes
Diabetic dyslipidemia refers to a cluster of lipid and lipoprotein abnormalities that are metabolically interrelated. In T2DM, increased large VLDL particles trigger a cascade of events resulting in atherogenic remnants, small dense LDL particles, and TG-rich HDL particles.383 Alterations in the composition of LDL and HDL particles affect their function. ApoC-III levels are increased, which impairs the clearance of TG-rich lipoproteins and their remnants, prolonging their circulation time382 and making them more atherogenic. This defective catabolism of TG-rich lipoproteins appears to be a more significant factor in increased plasma TG than increased production rates, resulting in an excess of remnant particles. This overall profile is also characterized by an increase in ApoB-containing particles. TG-rich lipoproteins — including chylomicrons, VLDL, and their remnants — carry a single ApoB molecule, just like LDL particles. As a result, the harmful nature of diabetic dyslipidemia is not always captured by standard lipid measures, since LDL-c levels may remain within normal limits. Thus, non-HDL-c or ApoB are better markers of TG-rich lipoproteins and remnants.43
9.3.2. Treatment of Dyslipidemia in Patients with Diabetes
Lifestyle Modifications
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Diet: A balanced diet rich in unsaturated fatty acids (eg, those found in olive oil, nuts, and avocados) and low in saturated and trans fats can help improve lipid levels. Adequate fiber intake is also important to reduce the levels of LDL-c and TG.
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Physical activity: Regular exercise — particularly aerobic and resistance training — can increase HDL and reduce TG. Exercise also improves insulin sensitivity.
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Weight loss: Reducing weight, especially visceral fat, can improve the lipid profile and insulin resistance.
9.3.3. Pharmacological Treatment
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Statins: LDL-c is the primary target of lipid-lowering therapy in patients with diabetes. Studies conducted specifically in individuals with T2DM, as well as subgroups of people with diabetes included in large statin trials, have consistently demonstrated significant CV benefits of statin therapy.384 According to the CTT meta-analysis, statin treatment reduces the incidence of major CV events by approximately 23% over 5 years for every 38.4 mg/dL reduction in LDL-c, regardless of baseline LDL-c or other characteristics.
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Ezetimibe: Ezetimibe may be used in combination with statins to further lower LDL-c levels, especially in patients at high CV risk. It reduces LDL-c by 24%, and when added to statin therapy, decreases the risk of major vascular events.385 The RR reduction is proportional to the absolute LDL-c reduction and consistent with the effect seen with statins. In the IMPROVE-IT trial, the diabetic subgroup had a higher rate of major CV events than those without diabetes (46% vs. 31%). Ezetimibe appeared particularly effective in patients with diabetes, with a 15% RR reduction (95% CI, 6%-22%) and a 5.5% absolute risk reduction.284
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PCSK9 inhibitors: In patients with diabetes and severe dyslipidemia and high CV risk, PCSK9 inhibitors (eg, alirocumab and evolocumab) are effective treatment options for lowering LDL-c. These drugs reduce LDL-c levels by approximately 60% and decrease the risk of major CV events.168 In the FOURIER trial, the RR reduction for CV events was similar in patients with and without diabetes; however, due to a higher baseline risk in those with diabetes, the absolute risk reduction was greater (2.7% reduction in major CV events over 3 years).196 Similar benefits were observed in patients with diabetes following ACS in the ODYSSEY trial.197 More recently, inclisiran has shown a substantial and sustained reduction in LDL-c across all glycemic and BMI strata.386
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Fibrates: Fibrates — agonists of PPAR-α — are potent lipid-modifying agents. Their main effects include lowering TG and increasing HDL-c levels. Several controlled trials have failed to show CV benefit, particularly when used as an "add-on" to statin therapy. However, subsequent analyses of large clinical trials, meta-analyses, and real-world data have proposed a potential role for fibrates in specific subgroups of patients with atherogenic dyslipidemia and MetS.387 Recently, in patients with T2DM, mild to moderate HTG, and low HDL and LDL-c levels, pemafibrate did not reduce CV event incidence compared to placebo, although it significantly lowered TG, VLDL cholesterol, remnant cholesterol, and ApoC-III.303 Despite this neutral outcome, there are indicators of potential benefit in microvascular ischemic complications such as PAD. Subsequent analyses showed a reduction in ischemic ulceration and gangrene of the lower limbs.388 Emerging data from the PROMINENT trial and experimental studies also suggest that pemafibrate may offer benefits in NAFLD and diabetes-related microangiopathy — topics that warrant further investigation.389 The LENS study evaluated the role of fenofibrate in patients with mild diabetic retinopathy. A total of 1,151 participants randomized to fenofibrate versus placebo were included. During a median of 4 years, retinopathy progression occurred in 131 (22.7%) of 576 participants in the fenofibrate group versus 168 (29.2%) of 575 in the placebo group (HR: 0.73, 95% CI 0.58-0.091, p=0.006).390
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Omega-3 fatty acids: Omega-3 supplements may be used to lower elevated TG and improve the lipid profile in diabetic patients. Omega-3 fatty acids — particularly EPA — have been studied for their ability to reduce TG levels. The REDUCE-IT trial showed that IPE, a purified form of EPA, reduced CV events in patients with T2DM and established CV disease with TG levels between 135 and 499 mg/dL.305 While other EPA studies have shown inconsistent results, REDUCE-IT is the most relevant for this population. A 4 g/day dose of IPE significantly reduced CV events in patients with diabetes and is considered effective, though platelet function monitoring is advised due to its antiplatelet effects.
The current guideline includes a specific risk and treatment flowchart for patients with diabetes, recognizing this group's high CV risk and distinct clinical characteristics. Lipid-lowering therapy in this population has a greater impact, given the elevated absolute risk of CV events. Thus, we recommend referring to the chapters on risk stratification, therapeutic targets, and treatment strategies. Primary targets should focus on LDL-c and, as a co-primary, non-HDL-c, along with the importance of measuring ApoB, especially in patients with diabetes due to the increased presence of atherogenic ApoB-containing particles.
9.4. Hypothyroidism
Hypothyroidism is a common endocrine disorder affecting approximately 4% to 10% of the population in its subclinical form and about 0.3%-0.4% in its clinical form. It is more prevalent in women, with a ratio of up to 4:1 compared to men.391,392 It is classified as clinical (increased TSH with low free T4) or subclinical (increased TSH with normal free T4). Both forms significantly affect lipid metabolism and CV risk.
Thyroid hormones — especially T3 — regulate hepatic expression of LDL receptors (LDL-R) and LPL activity. In hypothyroidism, reduced LDL-R expression leads to impaired LDL-c clearance and increased plasma levels of LDL-c.393 Decreased LPL activity contributes to impaired TG clearance and resulting HTG. Additionally, increased levels of Lp(a) and accumulation of small dense LDL particles — more atherogenic in nature — are observed.394,395
These changes result in a pro-atherogenic lipid profile, even in patients with subclinical hypothyroidism. The pro-inflammatory state associated with hypothyroidism, along with endothelial dysfunction, also fosters an environment conducive to CVD development.
Studies have shown that persistently elevated TSH is associated with increased CIMT, arterial stiffness, and a higher incidence of CV events, such as MI and stroke.396 Dyslipidemia caused by hypothyroidism is also often less responsive to statins until thyroid function is restored.397
Levothyroxine therapy is indicated in all cases of clinical hypothyroidism. In subclinical hypothyroidism, hormone replacement should be considered when TSH ≥10 mIU/L or in patients with typical symptoms, established CVD, diabetes, or multiple risk factors.398 Treatment is also recommended for patients with subclinical hypothyroidism and TSH between 4.5 and 9.9 mIU/L when dyslipidemia is present.399 Laboratory parameters should be monitored periodically — typically after 6-8 weeks — to adjust the levothyroxine dosage and assess treatment response. Normalization of thyroid function generally improves the lipid profile, particularly by reducing LDL and TC levels.399
Importantly, until thyroid hormone levels are normalized, patients may be more vulnerable to statin-related side effects such as myalgia or, in rare cases, rhabdomyolysis. Hormonal replacement and normalization of TSH and free T4 levels generally reduce these risks, making statin use safer.
The decision to initiate statin therapy should be individualized, considering overall CV risk, thyroid treatment response, and close monitoring of adverse effects.
On the other hand, hyperthyroidism is generally associated with a hypolipidemic profile, characterized by reduced total cholesterol, LDL-c, and TG due to increased LDL-R expression and accelerated hepatic lipoprotein metabolism.393 However, HDL-c levels may also decrease, attributed to increased CETP activity.
9.5. Chronic Kidney Disease
CKD is recognized as an important independent CV risk factor. The association between CKD and CVD is one of the leading causes of morbidity and mortality among dialysis and kidney transplant patients.400 Dyslipidemias in patients with CKD present distinct characteristics compared to those in the general population. These lipid metabolism alterations are primarily characterized by reduced LPL activity, HTG, accumulation of remnant lipoproteins (VLDL and IDL), elevated LDL, and changes in HDL composition and function. These abnormalities, combined with chronic inflammation and oxidative stress, significantly increase atherogenic risk — even in individuals with normal total cholesterol or LDL-c levels — which complicates risk stratification using traditional parameters.401,402
Therapeutic management is therefore critical to reduce CV risk, slow CKD progression, and address chronic inflammation. It also indirectly contributes to the control of associated conditions such as diabetes and MetS.
The primary therapeutic strategy involves the use of statins, with or without ezetimibe, aiming to reduce absolute CV risk regardless of specific LDL-c targets, especially in patients with reduced GFR.55,403-405 The combination of statin and ezetimibe has shown additional LDL-c reduction in pre-dialysis patients.406,407 In dialysis patients, particularly those undergoing peritoneal dialysis, statin therapy may be initiated in individuals at very high CV risk, as lipid metabolism is relatively preserved, potentially increasing the benefit of pharmacologic treatment.55,400,401 For those on hemodialysis, the benefits of initiating lipid-lowering therapy remain controversial, and there is concern regarding potential drug interactions and adverse effects. However, for patients already receiving lipid-lowering therapy prior to starting dialysis, continuation is recommended.400,406-409 In kidney transplant recipients, CV risk is elevated due to both traditional risk factors and adverse effects of immunosuppressive therapy. Statin use is associated with reduced CV events and mortality.401 Simvastatin and atorvastatin are metabolized via hepatic CYP3A4, which can lead to relevant interactions with immunosuppressants such as cyclosporine. Therefore, statins with lower interaction risk — such as pravastatin, fluvastatin, or rosuvastatin — are preferred.401 Lipid-lowering therapies other than statins lack robust data in the CKD population. Other interventions — including a balanced diet low in saturated fat, smoking cessation, regular physical activity, and weight control — have proven benefits for lipid profile, endothelial function, and comorbidity management, and should be part of comprehensive patient counseling.55,401,403,404
9.6. Obesity
Dyslipidemia and obesity are highly prevalent clinical conditions worldwide and are associated with significant morbidity and an increased risk of major CV events. The coexistence of these conditions amplifies metabolic disturbances, fostering a pro-atherogenic, inflammatory environment conducive to macrovascular ASCVD.
Combining obesity and dyslipidemia substantially increases the risk of CAD, stroke, HF, and PAD.410,411 The typical lipid pattern in individuals with obesity — HTG, low HDL-c, and small dense LDL particles — represents the lipid phenotype most strongly associated with MetS and accelerated atherogenesis.412 Excess adipose tissue, particularly visceral fat, promotes insulin resistance via inflammatory adipokines such as TNF- and IL-6, and reduced levels of adiponectin.413 This resistance leads to increased lipolysis and circulating free fatty acids, which are transported to the liver, resulting in increased VLDL production and HTG.413 Studies show that a body weight loss of 5%-10% already leads to significant improvements in lipid and glycemic profiles.414
Nonpharmacological interventions are essential and constitute first-line therapy. Recommendations include a calorie-restricted, balanced diet low in saturated fat (< 7% of total calories), increased intake of soluble fiber and phytosterols, and at least 150 minutes of moderate-intensity aerobic exercise per week.415
The need for pharmacological lipid-lowering therapy depends on the lipid profile and calculated CV risk. Statins have well-established benefits in reducing CV morbidity and mortality and should form the foundation of treatment when LDL-c is elevated, regardless of obesity status.416 Ezetimibe may be added to statins when stricter LDL-c targets are required.165 PCSK9 inhibitors are indicated for patients at very high CV risk or with FH and refractory LDL-c despite maximally tolerated treatment. Fibrates are primarily used in cases of HTG ≥ 500 mg/dL to reduce the risk of pancreatitis.303
GLP-1 receptor agonists — such as liraglutide and semaglutide — not only promote significant weight loss but also improve the lipid profile, contributing to modest yet consistent reductions in TG and TC.417 Recent evidence from the SELECT trial showed that in patients with established CVD and very high CV risk, semaglutide 2.4 mg significantly reduced major CV events, independently of weight loss, which reinforces its role as a cardioprotective agent beyond its weight-related effects.219,418
Bariatric surgery remains the most effective intervention for sustained weight loss and significantly improves metabolic parameters — including marked reductions in LDL-c and TG, increased HDL-c, and improved insulin resistance.419
9.7. Older Individuals
The risk of CVD increases with age,420 as does the risk of nonCV mortality, inevitably reducing life expectancy. For older adults, the treatment of risk factors for CVD must be carefully evaluated to balance benefits and risks, as these factors may differ among individuals with limited life expectancies.421,422 Importantly, older adults generally face a higher risk of adverse events and drug side effects.423,424 Therefore, identifying those who may benefit from preventive treatment is crucial.
The decision to initiate lipid-lowering therapy in older adults must consider specific factors such as drug pharmacokinetics, lower levels of clinical evidence for certain age groups, and the high prevalence of SAD in individuals over 65 years of age.425
Levels of TC are generally higher until the sixth decade of life, decreasing slightly with age. Even in genetic dyslipidemias, significant elevations in TC, TG, and LDL-c are uncommon. Secondary dyslipidemias are more frequent and may be due to hypothyroidism, diabetes, glucose intolerance, obesity, nephrotic syndrome, or medications such as thiazide diuretics and nonselective beta-blockers. The association between high cholesterol levels and increased risk of CAD in middle-aged and early older adults weakens with advancing age426 — likely a consequence of frailty orcompetitive events. In the Prospective Studies Collaboration, which included 61 prospective observational studies, the association between TC and vascular mortality was demonstrated in 900,000 individuals with no history of vascular disease, aged 40 to 89 years. The relative risk reduction of ischemic heart disease for each 39 mg/dL reduction in total cholesterol was smaller in older age groups, but as the absolute rate of this event increased with increasing age, there was a greater absolute difference in the oldest age group.
Although stronger evidence supports the role of dyslipidemias in the pathogenesis of atherosclerosis and CAD in middle-aged individuals based on observational and experimental studies,427 later studies have provided relevant findings that may support the treatment of dyslipidemia in the older adults as well.428 In older adults, treatment decisions must consider the patient's overall health and mental status, socioeconomic conditions, family support, comorbidities, and concurrent medications, which may interact with lipid-lowering therapies and influence adherence and treatment continuity.429
9.8. Nonpharmacological Treatment
Recommendations for nonpharmacological therapy should follow the same principles applied to younger adults considering the caloric, protein, and vitamin needs of older individuals. Additionally, the recommendation for regular physical activity should be included.
9.9. Pharmacological Treatment
Statins are the first-line pharmacological agents in this population. Evidence from studies involving older adults — such as the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial using pravastatin,430 the Heart Protection Study with a large sample of individuals over 65 years old,431 an exploratory analysis of the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial in individuals aged 70 and older,432 and the HOPE-3 trial, in which half the patients were over 65433 — as well as a meta-analysis by the Cholesterol Treatment Trialists (CTT) collaboration,166 all demonstrated a RR reduction in CV events in this subgroup receiving statin therapy.
The EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) trial evaluated the efficacy of ezetimibe in preventing CV events in individuals over 75 years of age and showed a reduction in the primary and secondary outcomes and coronary revascularization, with no difference in all-cause mortality or stroke.434
The STAREE (Statins in Reducing Events in the Elderly) trial435 is currently investigating the effects of statin therapy for primary prevention of CV events and mortality reduction in healthy individuals over 70 years of age. Results are expected to be available in 2025.
The US Preventive Services Task Force states that there is insufficient evidence to support initiating the treatment of dyslipidemia in adults over 75 years old without a prior history of CVD.436
The SCORE2-OP, recommended by the ESC to estimate CV risk in individuals over 70, may support treatment decision-making in this population.159
Therefore, the treatment of dyslipidemia in older adults should be tailored to the individual, accounting for factors such as comorbidities, life expectancy, and potential drug interactions. Treatment should be recommended for individuals at high or very high CV risk, with similar targets to those for younger individuals.
9.10. Children
Atherosclerosis is a progressive process that begins in childhood and is enhanced by factors such as increased cholesterol, obesity, and MetS — conditions that increase CV risk in adulthood. Knowledge about dyslipidemias in children has advanced significantly, enabling earlier diagnosis and more effective therapeutic approaches. Notably, LDL-c targets in this age group differ from those used in the adult population, being more lenient and adjusted to the developmental stage. The primary goal remains early prevention, ensuring safety and effectiveness while avoiding both the progression of atherosclerosis and adverse effects on growth and metabolic maturation.
9.10.1 Lipid Profile in Childhood
In children and adolescents, the assessment of lipids should be conducted after 8-9 hours of fasting and should include TC, HDL-c, TG, and LDL-c, which can be calculated or directly measured.437
9.10.2. Screening
Universal screening: between ages 9-11 and 17-21, preferably while fasting, regardless of family history.438
Selective screening: between ages 2-8 and 12-16 in children with risk factors such as:438
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Family history of hypercholesterolemia or premature CVD
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Overweight/obesity
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Diabetes, hypertension, or tobacco use
9.10.3. Primary Dyslipidemias
These are genetic, present from an early age, and can be monogenic or polygenic. The main forms are:
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HeFH;87
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A dominant genetic disorder characterized by increased LDL-c from birth;
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Affects 1 in every 250-300 individuals and is among the most common inherited causes of CVD;439
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Caused by mutations in genes such as the LDL receptor, ApoB, PCSK9.439,440
Diagnosis: LDL-c > 190 mg/dL or > 160 mg/dL with a positive family history. Genetic testing is useful but can be replaced by phenotypic evaluation. LDL-c should be measured at least twice over a 3-month period.87
Treatment: Includes diet, physical activity, and statin therapy, which should begin between ages 8-10 (or even earlier in severe cases). Statins reduce LDL-c by an average of 32% and are safe. Studies show that early initiation significantly reduces future CV events. The therapeutic goal is LDL-c < 130 mg/dL.441,442
Additional therapies:
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Ezetimibe can reduce LDL-c by up to 27% and may be combined with statins;443
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PCSK9 inhibitors (eg, evolocumab and alirocumab) are indicated in resistant cases or in statin intolerance;
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Evolocumab reduces LDL-c by approximately 44% in children and adolescents. Both are approved for pediatric use.444
9.10.4. Homozygous Familial Hypercholesterolemia
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A rare, severe form (1:300,000) caused by mutations inherited from both parents;84
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LDL-c levels are typically > 400 mg/dL, with early xanthomas and a high risk of CVD during childhood;84
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Diagnosis: Based on extremely elevated LDL-c, clinical signs, and family history. Genetic testing confirms the condition and guides treatment and family screening;84
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Treatment:
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LDL-c goal: < 115 mg/dL, with a lower target in those with established ASCVD, although difficult to achieve.84
9.10.5. Hypertriglyceridemias
These result from increased VLDL production or reduced lipolysis. TG levels between 175-885 mg/dL are considered mild to moderate; levels > 885 mg/dL are classified as severe. Secondary causes include poor diet, endocrine disorders, medications, and alcohol consumption.313,445
Treatment includes: lifestyle interventions – diet and physical activity; and pharmacotherapy – statins (reduce TG by up to 30%) can be initiated from age 10; fibrates and omega-3 fatty acids may be used when TG > 400 mg/dL.445
9.10.6. Monogenic Hypertriglyceridemia (Severe Hypertriglyceridemias)
FCS: a rare autosomal recessive disorder caused by mutations in the LPL gene and related genes. FCS typically manifests in childhood with TG levels > 1,000 mg/dL, recurrent pancreatitis, lipemia retinalis, and xanthomas. Treatment includes a diet with severe fat restriction (8%-10% of total calories) and use of medium-chain fatty acids.97
MCS: caused by multiple genes and worsened by factors such as diabetes, obesity, and certain medications. It is more common than FCS and responds well to lifestyle changes and treatment of comorbid conditions.97
9.10.7. Secondary Dyslipidemias
These are caused by underlying diseases or medications. The most common include:437
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T1DM and T2DM
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Hypothyroidism
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CKD
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Lupus
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Isotretinoin, corticosteroids, oral contraceptives
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Liver disease
Treatment of the underlying condition usually leads to normalization of the lipid profile.
9.10.8. Statin Therapy is Indicated Based on risk in Secondary Dyslipidemias, Particularly in High-Risk Conditions or in the Presence of Risk Factors (Threshold Values for Initiating Treatment)
Children > 10 years:
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LDL-c ≥ 130 mg/dL with multiple risk factors (eg, diabetes and hypertension)
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LDL-c ≥ 160 mg/dL with one risk factor, such as family history of premature heart disease or multiple mild risk factors (eg, untreated hypertension or obesity)
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LDL-c ≥ 190 mg/dL with no risk factors
9.11. Transplant Recipients
Advances in rejection therapy for transplant recipients have significantly improved survival rates, making CVD the leading cause of mortality.446 In this context, dyslipidemia plays a central role, being highly prevalent among solid organ transplant recipients. It is estimated to occur in up to 80% of kidney transplant recipients, 70% of liver recipients, and 50% of heart recipients, while prevalence in the general population is around 35%.447,448
Although factors such as genetic predisposition and pre-existing comorbidities contribute to lipid abnormalities, the primary causal factor is the use of immunosuppressants, especially calcineurin inhibitors (eg, cyclosporine and tacrolimus) and corticosteroids. These agents elevate levels of LDL-c and TG and are also associated with hypertension, insulin resistance, hyperglycemia, and diabetes. While drugs like azathioprine appear to have a neutral impact on lipid metabolism, the effects of newer therapies such as monoclonal and polyclonal antibodies still lack robust data.448-450
Cyclosporine, approved in 1983, revolutionized immunosuppression but adversely affects cholesterol metabolism: it inhibits CYP27A1, reducing bile acid synthesis and hepatic cholesterol excretion; interferes with LDL-c receptor binding; reduces LPL activity; and directly impairs pancreatic beta-cell function, inducing apoptosis and reduced insulin secretion. The dyslipidemia it causes is similar to that of corticosteroids, though with greater LDL-c increase.451
CVDs are the leading cause of death after heart and kidney transplants, and the second most common in liver transplants.448-450 In heart transplantation, graft vasculopathy stands out — an aggressive form of atherosclerosis characterized by concentric intimal hyperplasia and progressive luminal narrowing, responsible for up to 10% of deaths.450
Although transplant recipients are not automatically classified as a distinct risk category, patients receiving solid organ transplants (eg, kidney, heart, and liver) are at significantly increased CV risk.
Therefore, statin therapy is strongly recommended, except during the first one to two months following liver transplantation. Because of the risk of drug interactions, it is recommended to start with low doses. Notably, simvastatin, lovastatin, and pitavastatin should be avoided in patients on cyclosporine. In such cases, the FDA also advises caution with atorvastatin, although studies suggest that 10 mg/day may be safe. Typical starting doses include 5 mg rosuvastatin, 40 mg pravastatin, or 40 mg fluvastatin, with gradual titration.446 The combination of lovastatin, simvastatin, or pitavastatin with everolimus, tacrolimus, or sirolimus should also be avoided due to the risk of rhabdomyolysis and liver toxicity.452,453
Ezetimibe is considered a safe alternative.55 To date, PCSK9 inhibitors have not been extensively tested in this population, although they theoretically do not pose significant drug interaction risks, as they do not rely on the cytochrome P450 system. However, clinical safety trials are needed.451
Managing dyslipidemia in transplant recipients requires individualized care, as the very drugs that prolong life are those that cause lipid disturbances. Careful statin use, with attention to drug interactions, is crucial. Managing dyslipidemia should be a priority, as neglecting this aspect may compromise long-term survival in these patients.
9.12. Chronic Liver Diseases
Statins are contraindicated in patients with decompensated liver disease or acute hepatic failure but are considered safe for lipid-lowering therapy in patients with compensated liver disease.454-456
9.12.1. Metabolic Dysfunction-Associated Steatotic Liver Disease
9.12.1.1. Definition
MASLD is defined as hepatic steatosis in adults who have at least one cardiometabolic risk factor (eg, overweight/obesity, T2DM, prediabetes, hypertension, or atherogenic dyslipidemia) in the absence of secondary causes.457
9.12.1.2. Prevalence and Cardiovascular Risk
MASLD is highly prevalent and associated with an increased risk of major CV events.
9.12.1.3. Reducing Cardiovascular Risk
Comorbidities associated with MASLD — such as hypertension, diabetes, obesity, and dyslipidemia — should be addressed.457 Statins are the first-line treatment, as they target the atherogenic dyslipidemia found in MASLD and reduce ASCVD morbidity and mortality in these patients.
9.12.1.4. Liver Outcomes
Cohort studies suggest that statin use in MASLD is associated with reduced all-cause mortality, reduced risk of hepatic decompensation, and lower incidence of hepatocellular carcinoma (HCC).458 Statins also appear to reduce the progression of liver stiffness (an indicator of fibrosis), both in patients with and without advanced liver disease.459 Meta-analyses and systematic reviews indicate that statins may improve liver function tests and reduce the degree of steatosis and fibrosis, likely due to anti-inflammatory and anti-fibrotic mechanisms.458
9.12.1.5. Safety
Statins should not be discontinued in patients with stable chronic liver disease and normal or mildly elevated liver enzymes (up to 3× ULN), as they do not promote disease progression. Liver function tests should be monitored periodically.339
Ezetimibe: The use of ezetimibe in MASLD remains controversial; however, combination therapy with a statin may be used according to standard indications to achieve therapeutic goal.460 Due to limited data, ezetimibe should be avoided in patients with more advanced hepatic dysfunction (eg, Child-Pugh B and C).
9.12.1.6. Intrahepatic Cholestasis
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterized by chronic inflammation and dyslipidemia.461 Elevated total cholesterol levels are mainly due to increased lipoprotein X, which is nonatherogenic and does not raise CV risk. Lipid-lowering agents are indicated in the presence of additional CV risk factors in this population.
Statins are not contraindicated in patients with compensated PBC but should not be used in decompensated liver disease.462 There is no evidence that statins reduce intrahepatic cholestasis markers in PBC.462 Studies have shown that ezetimibe is safe in patients with PBC and, when combined with statins, may be considered for patients with PBC and CV risk factors.461
9.12.1.7. Hepatic Cirrhosis
While cirrhosis was once thought to protect against atherosclerosis, it is now known that the prevalence of CAD in cirrhotic patients may be higher than in the general population. CV risk varies by the etiology of the liver disease and is higher in cirrhosis caused by alcohol, HCV (hepatitis C virus), and NASH.463 Statins are safe and may be used in patients with Child-Pugh Class A and B cirrhosis.463-465
However, in Child-Pugh Class C cirrhosis, statins are not advised due to moderate to severe liver dysfunction, which impairs drug metabolism and increases serum levels, raising the risk of adverse effects.463,464 Current evidence on the benefits of statins in reducing portal hypertension and hepatic decompensation in cirrhotic patients is scarce; thus, statins are not indicated for these outcomes.463
Ongoing RCTs are evaluating the impact of statins on liver outcomes in cirrhosis.
9.12.1.8. Hepatocellular Carcinoma
Case-control studies, primarily among patients with viral hepatitis, have shown a 25% reduction in HCC incidence among users of lipophilic statins compared to nonusers.463 Meta-analyses suggest statin therapy is associated with a reduced incidence of HCC; however, randomized prospective data are still needed.
9.13. Acute Coronary Syndrome
Intensive cholesterol control after an ACS is a key pillar of prevention in individuals classified as very high-risk within the CV risk continuum. In recent decades, robust evidence has reinforced the importance of early initiation of potent lipid-lowering therapy, which has been proven to reduce recurrent CV events and mortality.
In 2005, Fonarow demonstrated that initiating statin therapy within the first 24 hours of hospitalization for ACS reduced early complications and in-hospital mortality.466 In 2008, Pitt et al. showed that LDL-c levels change minimally during the first 4 days after the event, validating early cholesterol measurement as a reliable therapeutic guide.467
These observations have led to the standard practice of providing lipid-lowering therapy during hospitalization. Studies with PCSK9 inhibitors (eg, alirocumab and evolocumab) have shown that LDL-c levels < 40 mg/dL are associated with sustained reduction in atherothrombotic events and have a good safety profile.203 Thus, the more intensive the LDL-c reduction, the greater the clinical benefit.
The SWEDEHEART registry showed that patients who reached their non-HDL-c goal within 2 months and maintained it long-term had lower risk, unlike those with slow treatment escalation.468
The AHA/ACC guidelines recommend a sequential and rational use of three drug classes: high-intensity statins, ezetimibe, and PCSK9 inhibitors. The timing of escalation depends on baseline LDL-c levels and prior statin use.403,469 The ESC proposes a similar approach, starting immediately with a high-intensity statin regardless of baseline LDL-c, followed by re-evaluation within 4-6 weeks. If the LDL-c goal is not achieved, ezetimibe should be added and if needed a PCSK9 inhibitor.55
The strategy proposed by the ESC Acute Cardiovascular Care committee — "Strike Early and Strike Strong" — supports starting a statin + ezetimibe during the acute ACS phase, with early addition of a PCSK9 inhibitor for patients at very high CV risk. This approach is based on three pillars: (1) high risk of CV events in the first 90 days; (2) traditional stepwise escalation may delay goal attainment by up to 12 weeks; and (3) imaging studies show plaque regression and stabilization with early use of alirocumab and evolocumab.332
Despite strong evidence, implementation in clinical practice remains suboptimal. Barriers such as clinical inertia, unfounded concerns about statins, geographic disparities, high costs of anti-PCSK9 therapies, and health system variability contribute to low adherence. These gaps are observed even in countries with strong public health care systems.
In the future, lipid management in ACS may include emerging therapies such as inclisiran, which acts via RNA interference and offers potential for early use and long-lasting effect. Furthermore, strategies to address residual risk — such as control of HTG and increased Lp(a) after LDL-c goal achievement — may enhance secondary prevention interventions.
The current guideline recommends early initiation of combination lipid-lowering therapy in ACS, with a high-intensity statin plus ezetimibe started during hospitalization. This strategy aims to reduce therapeutic inertia, increase goal attainment for LDL-c, and provide more effective CV risk reduction. Lipid profile reassessment should occur between 4 to 6 weeks, at which point anti-PCSK9 therapy is indicated if LDL-c goals have not been achieved. In individuals at extreme CV risk, this combined approach from the beginning of hospitalization is especially recommended.470
9.14. Immune-Mediated Diseases
Patients with immune-mediated diseases such as rheumatoid arthritis (RA), SLE, spondylarthritis, and psoriasis have a significantly increased CV risk,471 comparable to that of individuals with T2DM. The systemic inflammation typical of these conditions not only causes endothelial dysfunction and accelerates atherosclerosis but also leads to qualitative and quantitative changes in lipoproteins. Oxidation of LDL-c and dysfunction of HDL-c are observed, making them pro-atherogenic even when serum levels are within the normal range.472 This "lipid paradox" may mask atherosclerotic risk and delay the initiation of preventive measures.
In addition, medications may contribute to secondary dyslipidemia. Glucocorticoids decrease HDL-c and increase TG and LDL-c.473 Immunosuppressants such as cyclosporine may also raise TC and TG.
Some diseases have particularities that increase dyslipidemia and CV risk. Psoriasis, for example, is associated with a higher prevalence of obesity, hypertension, and diabetes.
Another factor to consider is disease severity and long-term control. Since traditional risk scores such as Framingham do not account for inflammatory status, CV risk is often underestimated in patients with immune-mediated diseases. Therefore, risk-adjusted approaches have been proposed for these populations.474
Overall, SLE, active RA, and moderate-to-severe psoriasis should be considered high-risk conditions for CVD, even in the absence of other risk factors. In cases of uncertain CV risk, CAC scoring via CT may be useful to guide therapeutic decisions.
Proper management of dyslipidemia requires a multidimensional approach, combining control of the underlying disease, lifestyle changes, and specific pharmacologic treatment. The first pillar of treatment is controlling inflammatory activity, which improves the lipid profile and reduces overall CV risk.475 Agents such as methotrexate and hydroxychloroquine tend to improve lipid levels indirectly by controlling inflammation.
Pharmacologic treatment of dyslipidemia in patients with immune-mediated diseases follows specific guidelines adapted to the increased risk in these patients. Therapeutic targets are usually more aggressive than in the overall population and also depend on risk enhancers such as nephropathy, prolonged use of corticosteroids, or a history of CV events.55
Statins are the first-line treatment due to their proven effectiveness in reducing CV events and their pleiotropic anti-inflammatory effects.476 In patients with statin intolerance or inadequate response, ezetimibe may be added, or in very high-risk cases, PCSK9 inhibitors.477
In addition to pharmacologic treatment, lifestyle changes are essential. These interventions are especially important because patients with immune-mediated diseases have a higher prevalence of associated risk factors such as physical inactivity and insulin resistance.
9.15. Pregnancy
During pregnancy, transient lipid profile changes (2nd and 3rd trimesters) include increases in TC and LDL-c (30%-50%), TG (50%-100%), and HDL-c (20%-40%).478
9.15.1. Gestational Dyslipidemia in Normolipidemic Women
Transient gestational dyslipidemias are the most prevalent (20%-30% of pregnant women). When occurring early (1st trimester), they increase TG-rich lipoproteins and lower HDL-c, raising the risk of preeclampsia, gestational diabetes, persistent postpartum hypertension, and long-term ASCVD.479 In fetuses, these changes are associated with prematurity, low birth weight, and macrosomia.480
9.15.2. Gestational Dyslipidemia in Women with Pre-Existing Dyslipidemia
HeFH: the most common genetic dyslipidemia, characterized by high LDL-c and early CAD risk.481 During pregnancy, levels of LDL-c increase significantly, especially since lipid-lowering therapies are stopped during pregnancy and breastfeeding. Despite high LDL-c levels, maternal-fetal outcomes do not differ between women with and without HeFH.4 No evidence suggests that treatment discontinuation during pregnancy increases long-term CV risk.482
HoFH: it is far rarer and is caused by two pathogenic variants that lead to markedly increased LDL-c. This condition predisposes individuals to early atherosclerosis and aortic valve/supravalvular disease. Hormonal changes and discontinuing treatment during pregnancy can further increase levels of LDL-c, complicating management. Nevertheless, maternal cardiac events are uncommon, and there are no prospective studies that assess the risk of CV morbidity or mortality due to therapy withdrawal during gestation.482
HTG: severe gestational HTG is defined as plasma TG > 1,000 mg/dL. It can be due to monogenic or polygenic causes, or secondary factors (eg, uncontrolled diabetes). Maternal risks include acute pancreatitis, hyperviscosity syndrome, and preeclampsia.483
9.15.3. Lipoprotein(a)
Lp(a) is a risk factor for both arterial and venous thrombosis. During pregnancy, it rises between the 10th and 35th weeks in 20%-30% of women.484 Structurally similar to plasminogen, elevated Lp(a) is associated with maternal complications (eg, preeclampsia) and neonatal risks (eg, preterm birth).484
9.15.4. Pharmacological Treatment
9.15.4.1. Statins
Safety: case reports described a high incidence of structural malformations — especially in the nervous and skeletal systems — in babies exposed to lipophilic statins during the first trimester.485
The FDA previously classified statins as category X drugs, banning their use during pregnancy and recommending discontinuation during conception attempts, pregnancy, and breastfeeding.486
9.15.4.2. New Evidence
Observational studies, systematic reviews, and meta-analyses have not shown an increase in the rates of congenital malformations or other harm in women exposed to statins during pregnancy. Systematic reviews and meta-analyses in women with hyperlipidemia or comorbidities and risk of preeclampsia have not demonstrated increased rates of congenital malformations or other adverse outcomes in pregnant women exposed to statins.487-490
In HoFH, a retrospective study compared pregnant women who continued statin therapy during pregnancy with those who discontinued it. No differences were found in overall pregnancy outcomes, CV complications, or congenital malformations between the two groups.491
New FDA Position: in pregnant women with significantly elevated cholesterol and CV risk, FDA argues that "the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients."486
Recommendation: statins should only be maintained during pregnancy for very high-risk patients and/or those with FH. This decision must be shared between physician and patient, considering the difficulty in assessing maternal risks of discontinuing the medication and potential fetal risks of maintaining it. While safety data on statin use during pregnancy has evolved, it remains extremely limited.
If statin therapy is maintained, it should be discontinued during the first trimester and reintroduced in the third trimester. Pravastatin is the statin with the strongest safety evidence.
9.15.4.3. Bile Acid Sequestrants
Bile acid sequestrants may be used during pregnancy and are not associated with an increased risk of congenital abnormalities. However, they are generally poorly tolerated and can impair the absorption of fat-soluble vitamins.492 There are reports of subdural hematomas in fetuses due to vitamin K deficiency in mothers under long-term cholestyramine therapy for intrahepatic cholestasis.492
9.15.4.4. Lipoprotein Apheresis
Extracorporeal removal of ApoB-containing lipoproteins by apheresis, when available, is the preferred treatment for HoFH.493
9.15.4.5. Ezetimibe
Not recommended during pregnancy or breastfeeding.494
New drugs: anti-PCSK9 therapies (evolocumab, alirocumab, inclisiran), ANGPTL3 inhibitors (evinacumab), BPA, and lomitapide are not recommended during pregnancy or breastfeeding.
Fibrates are not recommended during pregnancy.494 However, there are a few case reports, especially from the second trimester onward. It is recommended to consider fenofibrate during the second trimester if TG > 880 mg/dL.
9.15.4.6. Omega-3 Fatty Acids
Recommendation: omega-3 fatty acids may be an effective option for patients with severe HTG, especially those at risk for pancreatitis (TG > 880 mg/dL).494
9.16. Women
Women share many traditional risk factors with men; however, these factors may have a different impact on women due to biological and sociocultural differences. Additionally, there are women-specific risk factors — often under-recognized in clinical practice14,495,496 — that should be considered risk enhancers,497 as detailed in the risk stratification chapter.
Throughout life, women's lipid profiles display distinct patterns influenced by hormonal and physiological factors. During the reproductive phase, lipid profile fluctuations occur across the menstrual cycle, with LDL-c peaking in the follicular phase and decreasing during the luteal phase. Oral contraceptives can raise levels of TC and TG. During pregnancy, TG can physiologically double and TC may increase by approximately 1.5 times. After menopause, the drop in estrogen leads to increases in LDL-c and TG, raising atherosclerotic risk.
Oral hormone therapy during menopause reduces LDL-c and increases HDL-c but may also raise TG levels — particularly with conjugated equine estrogens or 17β-estradiol combined with progestins such as medroxyprogesterone acetate. Transdermal therapy has a neutral effect on TG, a lower hepatic impact, and preserves the positive effect on HDL-c.
Since women have specific risk factors related to hormonal changes and life stages such as pregnancy and menopause, identifying and accounting for these risk enhancers is strongly recommended by the current guideline and is fundamental to personalized risk stratification. Factors such as persistent dyslipidemia, early family history, and SAD should guide the adoption of effective therapeutic targets, without distinction between men and women. Regardless of sex, intensive treatment should be indicated according to the risk category, aiming to reduce LDL-c to guideline-recommended levels, using high-potency statins, combination therapy with ezetimibe, and, when necessary, anti-PCSK9 therapies. This therapeutic equity is essential to overcome clinical inertia and historical undertreatment, thereby expanding effective CV protection in women.
10. Conclusion
The 2025 Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis represents a decisive step toward effectively reducing CV risk across all life stages. On the basis of solid scientific evidence, the guideline moves beyond the traditional approach focused solely on dyslipidemia and embraces a broader vision of ASCVD prevention, integrating implementation strategies, imaging tools, and innovative biomarkers.
The 10 key messages (Figure 10.1) in the current guideline consolidate the pillars of modern prevention: from promoting healthy lifestyles and assessing risk with new markers such as Lp(a) and ApoB to recognizing specific risk profiles, including risk enhancers and the category of extreme CV risk, with the adoption of more aggressive and individualized treatment targets. The lowering of LDL-c targets in individuals at low short-term risk acknowledges the importance of early and sustained LDL-c control. The inclusion of tools such as PREVENT and CAC scoring enhances the ability to reclassify and personalize care.
In this new landscape, lipid-lowering therapy has evolved into a more robust and strategic arsenal, with an emphasis on reducing CV risk rather than merely correcting laboratory lipid levels. The recommendation of early combination therapy with statins, ezetimibe, PCSK9 inhibitors, and, in selected cases, BPA reflects the urgency of implementing intensive and safe interventions that improve therapeutic efficacy — especially in settings of poor adherence, statin intolerance, or difficulty achieving lipid targets.
By recognizing atherosclerosis as a progressive and silent condition that begins early and is influenced by multiple social, genetic, and clinical factors, the current guideline reinforces a commitment to a continuous and integrated approach throughout the life course. More than a technical document, it aims to serve as a tool to transform clinical practice in Brazil, promoting equity, scientific advancement, and a direct impact on population health.
Ultimately, the Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis reconnects treatment with its true purpose: to prevent CV events, save lives, and offer future generations a longer and better life.
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Execution:
Sociedade Brasileira de Cardiologia (SBC)
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General Coordinator:
Fabiana Hanna Rached
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Committee Members:
Fabiana Hanna Rached, Marcio Hiroshi Miname, Viviane Zorzanelli Rocha, André Zimerman, Fernando Henpin Yue Cesena, Andrei Carvalho Sposito, Raul Dias dos Santos, Paulo Behr, Henrique Tria Bianco, Renato Jorge Alves, Jose Francisco Kerr Saraiva.
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SBC Clinical Practice Guidelines Committee:
Pedro Gabriel Melo de Barros e Silva (Coordenador), Helena Cramer Veiga Rey, Humberto Graner Moreira, José Augusto Soares Barreto Filho, Nadine Oliveira Clausell – Period 2025-2027.
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Esta diretriz deverá ser citada como:
Rached FH, Miname MH, Rocha VZ, Zimerman A, Cesena FHY, Sposito AC., et al. Brazilian Guideline on Dyslipidemias and Prevention of Atherosclerosis – 2025. Arq Bras Cardiol. 2025;122(9):e20250640.
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Note:
These guidelines are for information purposes and should not replace the clinical judgment of aphysician, who must ultimately determine the appropriate treatment for each patient.
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