- ACC/AHA Cholesterol Guidelines: How to Handle the High-risk Patients?
- Consensus of ESC Lipid Guidelines: What is Applicable for Indians?
- Familial Hypercholesterolemia
- Understanding and Applying Latest Lipid Guidelines in Clinical Practice
- What are Top 6 Cardiovascular Prevention Trials on Lipid Lowering?
- Targets in Lipid-lowering Therapy Today
- Update on Lipid Management for ASCVD Prevention: What is New in the Cholesterol Guidelines?
- The Nuances of Statin Therapy for ASCVD in Clinical Practice
- Controversies to Consensus in Classification of Hyperlipidemias and Importance of Statins
- How to Enhance Practice and Implementations of Lipid-lowering Guidelines and Adherence?
- Comparison of Cholesterol Guidelines in Secondary Prevention and CVD Outcome: What is the Consensus Today?
- Current Status, Efficacy, Safety, and Outcome Data of Statin: Atorvastatin versus Rosuvastatin in CVD Outcome
- Current Place of Rosuvastatin/Ezetimibe Combination in Management of Hypercholesterolemia
- Risk Factors of Dyslipidemia
- Pathophysiology of Dyslipidemia
- Pleiotropic Effects of Statins and CVD Outcomes
- Dyslipidemia in Diabetes: Management Strategies
- High-dose versus Low-dose Statins in Cardiovascular Diseases
- Statin for Primary Prevention of Cardiovascular Disease
- Statin for Tertiary Prevention of Cardiovascular Disease
- Dyslipidemia and Statin: An Overview
- Efficacy, Safety, and Promising of Atorvastatin versus Rosuvastatin in LDL Cholesterol Reduction Potential and CVD Protection
- Statins and Angiogenesis
- Statin in Stress-induced Dyslipidemia
- Statin in Polyvascular Disease
- Statin and Sexual Dysfunction
- Statin and Erectile Dysfunction
- Statin and Nonalcoholic Steatohepatitis
- Statins and Hyperthyroidism
- Lipid Lowering in Nonalcoholic Fatty Liver Disease
- Statins in Cushing's Syndrome
- Statin and Gallstones Disorder
- Dyslipidemia in Pregnancy
- Statins and Inflammatory Markers
- Grow younger and Live Longer with Statin: Effect on Vascular Age
- Oxidative Stress and Statin Therapy
- Impact of Statins on Endothelium and Vascular Biology
- Exercise, Dyslipidemia, and Statin Therapy
- Role of Statin Drugs for Polycystic Ovary Syndrome
- Statin in Dyslipidemia and Hearing Loss
- Statins Intolerance: Is it Really a Problem?
- New Insights into Managing Symptoms during Statin Therapy
- Nutrition versus Statins: Where do we Stand?
- Cholesterol Confusion and Statin Controversy
- Statin Therapy in the Perioperative Period
- Statin Therapy in Cardiac Intensive Care
- Pharmacogenomics of Statin Response
- Advances in Statin Therapy and Beyond in Dyslipidemia-inflicted CAD Mortality Reduction
- The Controversy of a Wider Statin Utilization
- Gender Disparity in Statin Therapy
- How Much Statin Intervention is Enough?
- Balancing Primary Prevention and Statin-induced Diabetes Prevention
- Statin Effect on Atherosclerotic Plaque
- All for “Statins” and Statins for All: An “Update”
- Triglycerides Reduction Strategies to Prevent CV Events
- Statin above the Age of 75 Years: Is it Relevant?
- Do Lp(a) Levels Contribute to CVD Risk? What are the Effects of Statin, PCSK9i, LDL Apheresis, and ASOs Therapy?
- Morbidity and Mortality Benefits of Statin Therapy in CVD
- Novel and Emerging Nonstatin Lipid-lowering Drugs
INTRODUCTION
The latest guidelines by the American College of Cardiology (ACC) and the American Heart Association (AHA) Task Force on clinical practice guidelines for cholesterol management were published in 2018,1 and reviewed in 2019 for primary prevention.2 Compared to 2013, the ACC/AHA cholesterol guidelines3 lay more emphasis on detailed risk assessment. There is a special attention to patient subgroups, consideration of the value of therapy, and an aim of creating personalized treatment plans for each patient. There has been an introduction of newer cholesterol-lowering agents (nonstatin drugs) such as ezetimibe and PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors mainly for secondary prevention in patients at very high risk of atherosclerotic cardiovascular disease (ASCVD) events. In this chapter, we have reviewed the current and previous guidelines and discussed about how to handle the high-risk patients, risk estimation, method of getting lipid profile, and ASCVD risk calculation.
By combining all major risk factors into a prediction equation, an individual's probability of developing ASCVD can be estimated by using ASCVD risk estimator tool. The predicted risk is divided into low risk (<5%), borderline risk (5–7.5%), intermediate risk (≥7.5–20%) and high risk (≥20%) by the ACC/AHA guidelines. The categories with highest overall risk [secondary prevention and primary LDL-C (low-density lipoprotein cholesterol) levels ≥ 190 mg/dL (≥4.9 mmol/L)] require prompt treatment to lower ASCVD risk.1
EVALUATION
Measurement of Lipid Profile
In adults who are 20 years of age or older and not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting baseline LDL-C. If the value of triglyceride is >400, a repeat lipid profile in fasting state is recommended. In adults who are 20 years of age or older and without a personal history of ASCVD, but with a family history of premature ASCVD or genetic hyperlipidemia, measurement of a fasting plasma lipid profile is reasonable as part of an initial evaluation to aid in the understanding and identification of familial lipid disorders.
Risk Enhancers
Several other factors are associated with increased ASCVD risk. These are called risk-enhancing factors. Projections of future risk derived from major risk factors and risk-enhancing factors can be used to adjust the intensity of LDL-lowering therapy. These are enlisted in Box 1; their presence helps to confirm a higher risk state and thereby supports a decision to initiate or intensify statin therapy. They are useful for clarifying which atherogenic factors are present in a particular patient.
MANAGEMENT
Nonpharmacological Measures
The management of lipid disorders includes lifestyle therapies including diet management, weight control, and physical activity. Patients should consume a dietary pattern that includes intake of vegetables, fruits, whole grains, and legumes. Healthy protein sources [low-fat dairy products, low-fat poultry (without the skin), fish/seafood, and nuts] can be used. They should limit intake of sweets, sugar-sweetened beverages, and red meats. Caloric intake should be adjusted to avoid weight gain, or in overweight/obese patients, to promote weight loss. Diet remains an important component of management of dyslipidemia.4
However, lipids levels can only be reduced by 10–20% with dietary precautions. These are supplements to statin therapy in high-risk individuals. There is very little role for dietary therapy alone in high-risk individuals. A low-fat and restricted-carbohydrate diet with increased protein intake is important for all Indian patients with dyslipidemia. Indians derive increased fats from whole milk dairy products and these need to be restricted. Indian cooking includes frying and heating of oils. This results in production of trans fats which are harmful. The use of vegetable oils, especially mustard oil and olive oil, is to be encouraged.
Adults should be advised to engage in aerobic physical activity three to four sessions per week, lasting on average 40 minutes per session and involving moderate-to-vigorous-intensity physical activity.
Pharmacological Measures
The mainstay of pharmacotherapy is statins. Prior to these the hypolipidemic drugs were weak and did not show significant mortality reduction. This included bile acid sequestrants and fibrates. The bile acid sequestrants had high gastrointestinal (GI) intolerance and caused only modest reduction in LDL. The fibrates (fenofibrate) primarily reduce triglycerides and have little effect on cholesterol and LDL levels. The statin therapy has consistently shown to be effective in reducing mortality in secondary prevention and in high-risk individuals for primary prevention.
Statin Therapy
The intensity of statin therapy is divided into three categories: (1) High intensity (lowers LDL-C levels by >50%), (2) moderate intensity (30–49%), and (3) low intensity (<30%) (Table 1). Statin therapy is usually well tolerated and safe. Most frequently occurring statin-associated side effects are statin-associated muscle symptoms (SAMS), new-onset diabetes mellitus, transaminitis, memory/cognition disturbances. The agents used are atorvastatin and rosuvastatin. Rosuvastatin is twice as effective as atorvastatin. These are generally very well tolerated and the risk of new-onset diabetes is very minimal. Even though the muscle symptoms are more often nonorganic, one should do creatine phosphokinase (CPK) levels. In case these are normal patient who need to be reassured and the statins can be continued.
Nonstatin Medications
This includes ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. The addition of ezetimibe to a statin regimen increases the magnitude of LDL-C lowering by approximately 15–30%.4,5 The addition of a PCSK9 inhibitor to a statin regimen has been shown to further reduce LDL-C levels by 45–70%.6,7 Ezetimibe reduces cholesterol absorption. It is safe to use and is generally used in 10 mg daily dosage. It has been shown in multiple studies to reduce LDL levels in patients who are already on high-intensity statin therapy. In fact it is the treatment of choice after statins since it is cost effective. The PCSK9 inhibitors are more effective but are very expensive and have to be used by subcutaneous route. Their initiation should be done only after thorough discussion with the patient regarding the cost.5
MANAGEMENT ACCORDING TO CLINICAL CONDITION
The management of lipid disorders depends upon the risk of the individual. The high-risk individuals are those with evidence of ASCVD. This includes patients with angina, postmyocardial infarction, postprocedure including percutaneous coronary intervention (PCI) and postcoronary artery bypass grafting (CABG), stroke, and peripheral vascular disease (PVD). Lipid management in these patients is a secondary prevention since all the individual with above disorders have ASCVD. These high-risk patients need high-intensity statins and often addition of other agents. Patients with severe hypercholesterolemia also need treatment. Diabetic patients have higher risk of CAD and threshold for starting lipid-lowering therapy is low. The above three categories are high risk.
Individuals who are at lower level of risk with consideration for primary prevention and other subgroups are also discussed as separate subgroups. The considerations in these five categories are discussed here.
- Secondary prevention in ASCVD
- Severe hypercholesterolemia
- Dyslipidemia in diabetes mellitus
- Primary prevention
- Other populations at risk
Secondary Prevention in ASCVD
The 2018 guidelines defined “very high risk” of future ASCVD events as a history of multiple ASCVD events or one major event plus multiple high-risk conditions as mentioned in Box 2.
In patients younger than 75 years with clinical ASCVD,8 the ACC/AHA strongly recommends high statin therapy in these group of patients whenever possible with goal of reduction in LDL-C levels by ≥50% (Flowchart 1). This percentage can be used to judge clinical efficacy. Absolute benefit from statin therapy depends on baseline LDL-C levels. The greatest absolute benefit occurs in patients with the highest baseline LDL-C levels. Percentage reduction of LDL-C levels is the most efficient means to estimate expected efficacy. In patients with clinical ASCVD in whom high-intensity statin therapy is contraindicated or who experience statin-associated side effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30–49% reduction in LDL-C levels. Guidelines also make a strong recommendation for clinicians to add ezetimibe to maximally tolerated statin therapy as a first step in lowering LDL-C further as depicted in Flowchart 1. In patients with clinical ASCVD who are judged to be very high risk and considered for PCSK9 inhibitor therapy when the LDL remains high despite maximally tolerated statin therapy and ezetimibe.
Severe Hypercholesterolemia
Patients with primary severe hypercholesterolemia [LDL-C levels ≥ 190 mg/dL (≥4.9 mmol/L)] have a high lifetime risk of ASCVD and decisions about statins in these patients do not require risk scoring. Patients with very high LDL-C ≥ 190 mg/dL (≥4.9 mmol/L) values are most likely to achieve the greatest benefit from evidence-based LDL-C-lowering therapy regardless of genetic mutation associated with familiar hypercholesterolemia (FH). Maximally tolerated statin therapy should be administered to patients with primary severe hypercholesterolemia as high-intensity statins provide greater ASCVD risk reduction than moderate-intensity statins or placebo. Bile acid sequestrants may be considered in patients with severe hypercholesterolemia who are taking maximally tolerated statins with or without ezetimibe with less than a 50% reduction in LDL-C levels and have fasting triglycerides ≤ 300 mg/dL. Addition of a PCSK9 inhibitor may be considered in patients who have a baseline LDL-C level ≥ 220 mg/dL (≥5.7 mmol/L) and an on-treatment LDL-C level ≥ 130 mg/dL (≥3.4 mmol/L) despite maximally tolerated statin and ezetimibe therapy after a clinician–patient discussion of the net benefits versus the costs of such therapy.
Dyslipidemia in Diabetes Mellitus
High-intensity statin therapy to maximize risk reduction is preferred for patients with diabetes mellitus at any age or if they have risk modifiers as mentioned in Box 3. Adults of 40–75 years of age with diabetes mellitus are at an intermediate or high-risk of their first ASCVD event and regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated. The occurrence of a first ASCVD event in patients of 40–75 years of age with diabetes mellitus is associated with increased morbidity and mortality compared with those without diabetes mellitus, which places a particularly high premium on primary prevention in those with diabetes mellitus in that age range; therefore, it is 6reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more.
Flowchart 1: Secondary prevention in patients with ASCVD.(ASCVD: atherosclerotic cardiovascular disease; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin-kexin type 9: RCT: randomized controlled trial)
Further ezetimibe can be added to maximally tolerated lipid-lowering therapy in patients with diabetes mellitus and 10-year ASCVD risk of 20% or higher to reduced LDL-C by 50% or greater.
Primary Prevention
The 2019 ACC/AHA guidelines on the primary prevention of cardiovascular disease addresses major issues related to cholesterol management and primary ASCVD prevention. Three major higher-risk categories are patients with:
- Severe hypercholesterolemia [LDL-C levels ≥ 190 mg/dL (≥4.9 mmol/L)]
- Adults with diabetes mellitus
- Adults of 40–75 years of age
Patients with severe hypercholesterolemia and adults of 40–75 years of age with diabetes mellitus are candidates for immediate statin therapy without further risk assessment (Flowchart 2). Adults with diabetes mellitus should start with a moderate-intensity statin, and if they have multiple risk factors, a high-intensity statin may be indicated. In other adults of 40–75 years of age, 10-year ASCVD risk should guide therapeutic considerations. The higher the estimated ASCVD risk, the more likely the patient is to benefit from evidence-based statin treatment. The risk discussion should also consider several “risk enhancers” (Box 1) that can be used to favor initiation or intensification of statin therapy. When risk is uncertain or if statin therapy is problematic, it can be helpful to measure coronary artery calcium (CAC) to refine risk assessment. The CAC score predicts ASCVD events in a graded fashion and is independent of other risk factors, such as age, sex, and ethnicity. Most patients with CAC scores ≥ 100 Agatston units have a 10-year risk of ASCVD ≥7.5%, a widely accepted threshold for initiation of statin therapy (Flowchart 2).7
Flowchart 2: The 2018 cholesterol clinical practice guidelines for primary prevention.(apoB: apolipoprotein B; ASCVD: atherosclerotic cardiovascular disease; hs-CRP: high-sensitivity c-reactive protein; CAC: coronary artery calcium; CRP: high-sensitivity C-reactive protein; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein a
Other Groups
Older adults: Older adults are more susceptible to statin-related risks. In adults of 75 years of age or older with an LDL-C level of 70–189 mg/dL, initiating moderate-intensity statin may be reasonable.
Young adults (20–39 years): Development of atherosclerosis in young adults most commonly is multifactorial and occurs most rapidly in individuals with multiple risk factors such as hypercholesterolemia, hypertension, cigarette smoking, diabetes mellitus, and obesity. Young adults with primary elevations of LDL-C ≥ 190 mg/dL have a long-term ASCVD burden and statin therapy is recommended. Young adults with persistent, moderate hypercholesterolemia (LDL-C 160–189 mg/dL) are at a higher risk, especially when associated with risk-enhancing factors, such as a family history of premature ASCVD. Clinical judgment suggests that these high-risk young adults will benefit from long-term statin therapy.
Children and Adolescents: In children and adolescents with a family history of either early CVD or significant hypercholesterolemia [LDL-C ≥190 mg/dL (≥4.9 mmol/L) with known primary hypercholesterolemia], it is reasonable to measure a fasting or nonfasting lipoprotein profile as early as age 2 years to detect FH or rare forms of hypercholesterolemia. In children and adolescents of 10 years of age or older with an LDL-C level persistently 190 mg/dL or higher (≥4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with FH and who do not respond adequately with 3–6 months of lifestyle therapy, it is reasonable to initiate statin therapy.
Ethnicity: It is reasonable for clinicians to review race/ethnic features that can influence the ASCVD risk, intensity of treatment and even lipid drug doses. Important examples include the heightened risk of ASCVD in those who are from South Asian race. There is an increased sensitivity to statins in East Asians. The prevalence of hypertension is higher in blacks.
REFERENCES
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–143.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.
- Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9(2):129–69.
- Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: The ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186–94.
- Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532–61.