Cardiovascular disease (CVD) is the leading cause of death among adults in the United States, and people with hyperlipidemia are at roughly twice the risk of developing CVD as compared to those with normal total cholesterol levels.1 Patients with familial hypercholesterolemia (FH) have an even greater risk of developing CVD at an earlier age; therefore, early detection and treatment are imperative to reduce cardiovascular events and premature death. Statins are the mainstay treatment for hyperlipidemia; however, the limitations of statins include treatment resistance, intolerance due to adverse events, and a lack of adherence which contribute to poor outcomes. As such, many patients require adjunct therapies to properly control hyperlipidemia including niacin, bile acid sequestrants, fibric acids, and ezetimibe. FH can be even more challenging to treat, often requiring the use of lomitapide, mipomersen, proprotein convertase subtilisin/kexin type 9 inhibitors, or low-density lipoprotein cholesterol apheresis, in addition to high dose conjunction with statins or other agents.2 The approach to determining the appropriate treatment options has also undergone important changes. Guidelines for the management of patients with hyperlipidemia vary in their recommendations, with the American College of Cardiology/American Heart Association recommending that treatment decisions be based on the intensity of response associated with various statins, while multiple other guidelines (eg, National Lipid Association (NLA) and the American Association of Clinical Endocrinologists and American College of Endocrinology) still support attaining prespecified lipid values to reduce cardiovascular risk.3-5 This article will review the epidemiology of hyperlipidemia and FH, risk factors associated with the development of disease, as well as the efficacy and safety of statins and adjunct treatment options.
Am J Manag Care. 2017;23:-S0
Hyperlipidemia involves an imbalance of cholesterol levels, including low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in the blood. LDL-C and HDL-C regulate the amount of cholesterol in the body and an imbalance can increase the risk of cardiovascular events, including myocardial infarction and stroke. Other forms of hyperlipidemia include hypertriglyceridemia as well as mixed hyperlipidemia, in which both cholesterol and triglyceride levels are elevated. Elevated LDL-C can lead to a buildup of plaques within the arteries and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease or stroke. As HDL-C functions to remove cholesterol from the body, increased levels of HDL-C (≥60 mg/dL) can help decrease the risk of ASCVD.6
In the United States, more than 100 million, or roughly 53% of adults, have elevated LDL-C levels.7 Yet, fewer than 50% of patients with high LDL-C receive treatment to reduce their levels, and among those receiving treatment, fewer than 35% achieve adequate control.1,7 Further, approximately 31 million American adults have total cholesterol levels that exceed 240 mg/dL, placing them at about twice the risk of ASCVD compared to those with total cholesterol levels that are at goal.1
Risk Factors for Hyperlipidemia
Several factors are associated with an increased risk of hyperlipidemia. Modifiable risk factors include a diet high in saturated or trans fats, physical inactivity, smoking, and obesity.1 Secondary causes of elevated LDL-C include diseases such as biliary obstruction, chronic kidney disease, type 2 diabetes mellitus, high blood pressure, and hypothyroidism.1 Medications such as diuretics, cyclosporine, and glucocorticoids can also contribute to elevated LDL-C levels.3 Data related to the role of race and gender in the development of hyperlipidemia have been conflicting; however, some risk factors may be more prevalent in specific races, such as obesity in non-Hispanic blacks, and thus an increased incidence of hyperlipidemia within that population.8 Predictions of 10-year and lifetime ASCVD risk, based on patient-specific risk factors, are available in the literature. Clinical tools such as the American College of Cardiology/American Heart Association (ACC/AHA) ASCVD risk calculator,9 can be useful in evaluating individual patient risk; however, clinicians using these resources should note that there are some limitations when using these risk predictors. The ACC/AHA has stated that the risk predictor could be used to predict stroke as well as coronary heart disease (CHD) events in non-Hispanic white and African American women and men 40 to 79 years of age. Beyond these parameters, the ASCVD risk calculator may not be a reliable predictor due to lack of sufficient data in other races or age groups. In addition, the calculator is not a reliable risk predictor for those with total cholesterol over 320 mg/dL, which would include patients with familial hypercholesterolemia (FH).
Genetics can also play a role in the development of elevated cholesterol in the form of FH. FH is an autosomal dominant trait characterized by significant elevations in total cholesterol and LDL-C from birth and premature ASCVD.10-13 DNA testing has revealed that FH is the result of genetic mutations in the LDL receptor (LDLR); gain-of-function mutations of the proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to decreased LDL metabolism; or genetic mutations in the apolipoprotein (apo) B gene, which reduces binding of LDL particles to the LDLR.14,15 Of the 3 types of genetic mutations listed above, the majority of individuals with FH have a mutation in the LDLR.16 A lack of enough properly functioning LDLRs results in a reduction of cleared LDL-C, and thus an increase in circulating LDL-C. Compared with patients without FH, those with FH have greater risk of developing coronary heart disease.17 A recent analysis by the National Health and Nutrition Examination Survey (NHANES) noted that although the prevalence of FH did not differ based on gender, the prevalence of FH did vary among ethnic groups, with the lowest prevalence among Mexican Americans and the highest prevalence among whites, blacks, and other Hispanics.18
There are 2 types of FH: homozygous (HoFH) and heterozygous FH (HeFH). In the United States, HeFH is more common, affecting approximately 1 in 500 people, and is associated with LDL-C levels of 200 to 450 mg/dL.19,20 Patients with HeFH often develop coronary artery disease before the age of 60 years.15 HoFH is rarer, affecting roughly 1 in 300,000 to 1,000,000 people, but is associated with much higher LDL-C levels compared with HeFH (450 to >1000 mg/dL).11,19,21 If left untreated, patients with HoFH may die before the age of 20 years.15
Management of Hyperlipidemia and FH
Statins reduce total cholesterol and LDL-C via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Multiple studies have clearly shown that statins can lower LDL-C levels, thereby reducing the risk of developing CVD in patients with elevated LDL-C and reducing mortality and disease progression among patients with clinical ASCVD.3,22-29 Statins are the mainstay of treatment for hyperlipidemia, including use in FH.3,4
Seven statins are currently approved by the FDA for the treatment of hyperlipidemia in combination with a heart-healthy diet.30-37 A meta-analysis of 26 randomized trials involving 170,000 patients treated with various statins showed that a decrease in LDL-C of 39 mg/dL was associated with a 24% risk reduction in major vascular events.29 The trials included patients being treated for either primary or secondary prevention of cardiovascular disease, and the duration of treatment was at least 2 years. In general, statins can reduce LDL-C by approximately 20% to 65% with greater reductions seen with atorvastatin, rosuvastatin, and pitavastatin; moderate decreases with lovastatin and simvastatin; and the lowest decreases with fluvastatin and pravastatin.22,24-28,35 All but pitavastatin have indications for patients with FH.
While statins are generally well tolerated, they are associated with numerous adverse effects, including gastrointestinal events, musculoskeletal pain, respiratory infections, and headaches.30-34,36,37 Statins can also be associated with elevated blood glucose and glycated hemoglobin (A1C) levels.38-40 Increases in liver enzyme transaminases can occur infrequently, and statins are contraindicated in patients with active liver disease, as well as in patients with unexplained and chronic elevations in liver enzyme transaminases. Caution is advised regarding the concomitant use of most statins and anticoagulants; a reduction in the dose of the anticoagulant is recommended.30-32,34,36,37
Approximately 10% of patients receiving statins experience muscle-related symptoms, including bilateral muscle pain, weakness, and inflammation.41-43 Results from studies have indicated that simvastatin, atorvastatin, and lovastatin are associated with a higher incidence of muscle-related adverse events, and pravastatin, fluvastatin, and rosuvastatin have the lowest rates.41,43,44 Serious adverse events, including myopathy and rhabdomyolysis, are less common, with an incidence of approximately ≤5 of every 1000 patients receiving statins. Severe rhabdomyolysis is a serious form of statin-induced myopathy that is associated with high elevations in serum creatinine kinase, myoglobinuria, and acute kidney injury, and may be life threatening.45 Concomitant use of various drug classes, such as strong CYP3A4 inhibitors, including macrolide antibiotics, HIV and hepatitis C protease inhibitors, gemfibrozil, cyclosporine, danazol, as well as some antifungals, antihypertensives, and antiarrhythmic agents can increase the risk of developing rhabdomyolysis, as can use of higher statin doses.30-34,36,37 Combinations of statins with either niacin or fibrates can also increase the risk of serious adverse events.46,47 Several factors, including older age (≥65 years), renal impairment, and uncontrolled hypothyroidism, can also contribute to the risk of rhabdomyolysis.
Limitations of Statins
While statin monotherapy can lower LDL-C levels in most patients, some patients are nonadherent, intolerant, or resistant, resulting in poor outcomes.
Nonadherence to Statin Treatment
Nonadherence to statin treatment is a common issue, and has been shown to lead to an increased risk of ASCVD and mortality.10,48-50 Studies have found that 10% to 30% of patients never fill their first statin prescription, and adherence rates are roughly 25% to 50% among patients with acute coronary syndrome and those receiving statins for primary prevention of ASCVD.51-57 Further, within the first year, approximately 50% of patients discontinue statin therapy, and discontinuation rates at 2 years can be ≥75%.10,58 Nonadherence and nonpersistence are associated with an increase in both ASCVD risk and mortality.50 Factors contributing to nonadherence include comorbidities, AEs, regimen complexity, age, sex, co-payment, and income.10,57,59,60 Data from a meta-analysis of 22 cohort studies revealed that patients ≥70 years and <50 years of age were more likely to be nonadherent compared with those 50 to 69 years of age.57 In addition, nonadherence was greater among women and patients with lower incomes. Conversely, better adherence was noted among patients with a history of myocardial infarction or stroke, hypertension, or diabetes. Recommendations for addressing nonadherence include assessing the number of missed doses per month and discussing any barriers to adherence with the patient.61 Medication therapy management, pharmacy disease management programs, and other pharmacist-driven efforts can help to improve clinical outcomes, improve adherence, and minimize cost.62
Statin intolerance is often associated with poor adherence. Results of a meta-analysis comparing high-intensity and moderate-intensity statins revealed an increased risk of adverse events and adverse event-related treatment discontinuation with higher intensity statins63; however, another more recent meta-analysis noted less risk with rosuvastatin.64 Patients drinking grapefruit juice, especially large quantities, should be reminded of the potential for an interaction with statins, metabolized by CYP3A4. In addition, drugs that affect the CYP3A4 pathway can alter the metabolism of statins that are major substrates of CYP3A4, such as simvastatin, atorvastatin, and lovastatin. This can result in muscle-related adverse events.65-68 Approximately 7% to 29% of patients receiving statins experience muscle-related adverse events, which can contribute to poor adherence and nonpersistence.41,69-71 Rhabdomyolysis is a severe and potentially fatal form of muscle-related adverse event that occurs at a rate of 3.4 per 100,000 person-years.72 A systematic review noted higher incidences of rhabdomyolysis among patients receiving simvastatin or atorvastatin as compared with pravastatin or fluvastatin, and among patients receiving fibrates in combination with statins.64 As pravastatin, fluvastatin, and rosuvastatin are only minor substrates of CYP3A4, these statins have a lower incidence of drug—drug interactions and also may be a better option for patients at an increased risk of developing rhabdomyolysis.64,73 In cases where musculoskeletal events occur in patients receiving statins, it is important to first verify that statins are the cause of the events.
Recommendations for management of skeletal-related events in patients receiving statins from the NLA include decreasing the dose of a daily statin, incorporating a once-weekly dose of a long-acting statin, such as rosuvastatin or atorvastatin, as well as switching to either a different statin or a nonstatin, such as ezetimibe or bile acid sequestrants (BASs).46 The ACC recommends discontinuing the statin and rechallenging to verify that the statin is indeed the cause of the muscle-related symptoms.61 In patients with unexplained severe muscle pain, test for rhabdomyolysis by evaluating creatine kinase and creatinine levels and perform a urinalysis for myoglobin.3 For mild to moderate muscle symptoms, it is recommended to discontinue the statin and determine the cause of the symptoms. If no causal relationship between the muscle symptoms and the statin is found, and there are no contraindications, the original statin can be given to the patient at either the original dose or at a lower dose.3 Finally, if a causal relationship between statin use and muscle symptoms is found, it is recommended to use a low dose of a different statin, increasing the dose until the maximum tolerated dose is determined.3 ACC has developed the ACC Statin Intolerance app, which is available as a Web version or application that can be accessed by smartphones or tablets. This ACC resource is based on recommendations in the 2013 ACC/AHA guideline and helps to direct clinicians through a detailed algorithm to help determine if severe muscle-related pain during statin therapy meets criteria for rhabdomyolysis and provides follow-up steps that should be taken after investigation of muscle-related AEs.74
Data from studies indicate an increased risk of high glycemic effects with higher doses of statins, especially among patients already at an increased risk of developing diabetes.75-77 Among patients receiving statins, the increased risk of diabetes incidence was noted with simvastatin, atorvastatin, and rosuvastatin as compared with pravastatin.78 Additionally, no increased risk of developing diabetes was noted among patients receiving fluvastatin or lovastatin. Patients with diabetes are often at an increased risk of ASCVD, especially without statin use. Guidelines, including those from the ACC/AHA, recommend statin therapy for patients 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL.3 The NLA Statin Safety Assessment Task Force notes that while there is a modest level of evidence correlating statin use with new-onset type 2 diabetes, there is a high level of evidence that the benefit of statins in reducing the risk of ASCVD outweigh the risk of developing diabetes.40 Rather than making specific recommendations for treating patients at an increased risk of diabetes, the NLA recommends that treatment decisions should be based on guidelines for the management of hyperlipidemia.40 It is important to discuss the benefits and risks of statin therapy with patients before initiating treatment.
Studies estimate that 30% of patients treated with statins, especially those with FH, did not reach LDL-C levels <100 mg/dL.79,80 Very high baseline levels, such as those seen in patients with FH, predispose patients to statin resistance.10 Data from studies indicate that statins can reduce LDL-C levels by 35% to 50% in patients with HeFH; however, in patients with HoFH, LDL-C levels are typically only reduced by 10% to 25%.81-86 A 25% to 50% reduction in LDL-C levels may not be adequate to achieve optimal LDL-C target levels in FH.82,86,87 For example, a study of rosuvastatin in children with FH demonstrated that although there was a 50% reduction in LDL-C among those receiving rosuvastatin 20 mg daily, only 40% of these patients achieved optimal LDL-C target levels.82 Thus, many patients with FH require additional therapies to attain optimal LDL-C levels to reduce the substantial ASCVD risk inherent to this condition.
Several nonstatin therapies are available as adjunctive treatment for patients who do not respond adequately to statins or for those who are intolerant of statins. These include BASs, fibric acids, niacin, cholesterol absorption and synthesis inhibitors, as well as the recently approved class, PCSK9 inhibitors.88-98
Bile Acid Sequestrants
BASs include cholestyramine, colestipol, and colesevelam. BASs reduce cholesterol by binding bile acids within the intestine, impeding bile acid reabsorption and enterohepatic cycling, increasing the conversion of cholesterol to bile acids, and increasing the number of hepatic LDLRs. This results in increased clearance of LDL-C and decreased LDL-C levels.88-90,99 Colesevelam monotherapy is associated with a 15% to 20% reduction in LDL-C.100,101 Studies have demonstrated that adding BASs to statins, fibrates, niacin, or ezetimibe can significantly reduce LDL-C levels compared with monotherapy.102-109 The addition of colesevelam to statins and/or ezetimibe can further reduce LDL-C levels in adults and children (ages 10 -17 years) with FH compared with statin monotherapy.110,111 In addition, a pooled analysis of 3 trials found that the combination of colesevelam and statins significantly decreased both LDL-C and A1C in patients with both hyperlipidemia and diabetes.112 The addition of colesevelam to therapy with atorvastatin and niacin led to a notable reduction in LDL-C (57%) compared with the combination of atorvastatin and niacin alone (47%).113 While most BASs-associated AEs are tolerable, caution is recommended when prescribing BASs for patients with complete biliary obstruction due to an increased risk of new or worsening constipation.88-90 Additionally, the labeling for some BASs can include a precaution regarding increased risk of bleeding. This risk exists when hypoprothrombinemia from vitamin K deficiency occurs due to reduction in absorption of fat-soluble vitamins related to chronic use of BASs.88-90 In patients receiving any other medications in combination with BASs, administration should be spaced either 1 to 4 hours before, depending on the other medication, or 4 to 6 hours after BAS administration to reduce the chance of impaired absorption.89 Oral vitamin supplementation should be taken at least 4 hours before colesevelam.90
Fibric Acid Derivatives
Fibric acid derivatives are peroxisome proliferator-activated receptor α (PPARα) agonists that have been shown to reduce triglycerides by ≤50%, increasing HDL-C by ≤15%, LDL-C levels by 15% to 25%, and reducing major coronary events.114-117 Similar to BASs, fibrates further reduce LDL-C levels when combined with statins compared with statins or fibrates alone.118-120 However, when used in combination with high-intensity statins, fibrates can increase the risk of myopathy and rhabdomyolysis.121 The incidence of skeletal adverse events is higher when combining high-intensity statins with gemfibrozil compared to fenofibrate.122 Guidelines recommend against using gemfibrozil in patients receiving statins, and fenofibrate should be restricted to patients receiving low-to-moderate dose statin therapy, as long as the benefits outweigh the risks.3 In addition, fibrates are contraindicated in patients with hepatic or renal disease, unexplained persistent liver function abnormality, and in those with preexisting gallbladder disease.91,92 Combination therapy of gemfibrozil plus repaglinide is also contraindicated.91 Additionally, fenofibrate is contraindicated while breastfeeding.92 Finally, caution is advised regarding the concomitant use of fibrates and anticoagulants, and increased monitoring of prothrombin time with international normalized ratio (INR) determination is recommended until these parameters have stabilized after 1 drug in this combination is added to the other.92
Niacin increases levels of HDL and reduces levels of very low-density lipoprotein (VLDL) which, in turn, reduces LDL-C levels.123 Studies involving the combination of niacin with statins have provided conflicting results.100,124-127 In general, the addition of niacin to statins is associated with increased HDL-C, but is not associated with a significant reduction in LDL-C compared with statin monotherapy. In addition, results from multiple studies failed to show that the addition of niacin could reduce the risk of cardiovascular events, and indicated an increase in the risk of adverse events in patients receiving high-intensity statins compared with statin monotherapy.128,129 The most common niacin-related adverse event is flushing. Laropiprant, a selective prostanoid receptor antagonist, can reduce the incidence and severity of niacin-related flushing when administered concomitantly.130,131 However, results from the HPS2-THRIVE phase 3 study demonstrated that adding extended-release niacin and laropiprant to statin-based treatment was associated with an increase in diagnosis of type 2 diabetes as well as serious gastrointestinal and musculoskeletal events, infection, and bleeding.129 Niacin is contraindicated in patients with active liver disease, peptic ulcer disease, or arterial bleeding.93 Due to the increased risk of myopathy and rhabdomyolysis in patients receiving niacin in combination with either lovastatin or simvastatin, it is recommended that the dose of these statins not exceed 40 mg in patients receiving niacin.93 Caution should be used when prescribing niacin to patients with renal or hepatic impairment. In addition, the ACC notes that due to the lack of efficacy and potential for harm, niacin is not recommended for the treatment of hypercholesterolemia.61
Ezetimibe reduces LDL-C by inhibition of cholesterol absorption in the intestines.94 Data from multiple clinical trials demonstrated the combination of ezetimibe and statins reduced mean LDL-C levels significantly more than either the statin or ezetimibe monotherapy.132-140 Ezetimibe used in combination with statins also has been shown to be efficacious in reducing LDL-C levels.141-147 In clinical trials, ezetimibe was found to be generally well tolerated.132-140 Ezetimibe is not recommended for patients with active liver disease who are taking statins.94 The ACC released an update in 2016 suggesting that ezetimibe should be the first nonstatin agent added to statin therapy when combination therapy is necessary.61
Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for use in combination with other lipid-lowering therapy, including diet and LDL apheresis in patients with HoFH.95 Approval of lomitapide was based on a single-arm, open-label, phase 3 study of 29 patients with HoFH who received lomitapide (5 mg to 60 mg/day) in addition to current treatment with lipid-lowering agents, including statins and/or nonstatins. After 26 weeks of treatment, lomitapide was associated with a 50% mean reduction of LDL-C levels in the intent-to-treat population.148 LDL-C levels were reduced by more than 20% in 83% of patients and more than 50% in 52% of patients. Statistically significant reductions in total cholesterol, triglyceride levels, and apo B levels were also noted. Common adverse effects include dyspepsia, abdominal pain, nausea, diarrhea, and vomiting.148 Gastrointestinal adverse reactions, which affect more than 90% of patients who take lomitapide, can be reduced by adhering to a diet with <20% of calories from fat. If diarrhea or vomiting occur with lomitapide, the absorption of concomitant oral medications can be impaired.95 It is recommended that daily dietary supplements of vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) be taken due to the reduction in absorption of fat-soluble vitamins that can occur during lomitapide therapy. Due to the risk of treatment-related hepatotoxicity, lomitapide is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.95 Lomitapide is contraindicated in pregnancy, in patients with moderate or severe liver impairment or disease, and in combination with moderate or strong CYP3A4 inhibitors.95 The risk of myopathy is increased when lomitapide is used concomitantly with simvastatin or lovastatin.
Mipomersen is an antisense oligonucleotide that inhibits apo B100 synthesis and is indicated as adjunctive therapy to lipid-lowering medications and diet to reduce LDL-C, apo B, total cholesterol, and non-HDL-C in patients with HoFH.96 Approval of mipomersen was based on a randomized, double-blind, placebo-controlled phase 3 study of patients (N = 51) with HoFH who were 12 years of age or older and were currently receiving lipid-lowering agents at the maximum tolerated dose.149 There was a 24.7% mean reduction in LDL-C in patients receiving mipomersen (n = 34) compared with 3.3% in patients receiving placebo (n = 17; P = .0003). Statistically significant reductions in apo B, total cholesterol, and non-HDL-C were also noted. Additional trials have demonstrated the efficacy of mipomersen in reducing LDL-C in patients with HeFH,150 severe HeFH,151 HeFH with coronary artery disease,152 and HoFH.148,153 Additional data indicate that mipomersen is efficacious in people with statin intolerance at high risk of ASCVD,154 and for those with severe hyperlipidemia at high risk of ASCVD.155 Common AEs associated with mipomersen include flu-like symptoms, injection-site reactions, headache, nausea, and alanine aminotransferase elevations.148-151,153-155 Similar to lomitapide, mipomersen is contraindicated in patients with moderate or severe liver impairment, and is only available through a restricted REMS program.96 Fortunately, mipomersen was not noted to have any clinically relevant drug interactions in clinical trials.
Recently, a new class of medications called PCSK9 inhibitors has been approved. Alirocumab and evolocumab are monoclonal antibodies that bind to PCSK9. Normally, PCSK9 binds to LDLRs and increases their degradation, resulting in higher LDL-C levels. By inhibiting PCSK9, more LDLRs remain in circulation, which then lower LDL-C. Both currently available PCSK9 inhibitors are approved as adjunct to diet and maximally tolerated statin therapy in adults with HeFH, or those with clinical ASCVD who require additional lowering of LDL-C.97,98 Both alirocumab and evolocumab are well tolerated and can reduce LDL-C levels in patients with HeFH, high baseline LDL-C levels, and statin intolerance.156-158 Promising results from studies combining alirocumab with various statins have also been published.159-163 Studies have demonstrated that evolocumab is effective for the treatment of patients with statin intolerance and patients with HeFH; evolocumab also has an added indication for treatment in adults with HoFH.164-167 Similar to alirocumab, evolocumab can further reduce LDL-C when combined with statins.168 Importantly, ACC/AHA recommendations include the use of PCSK9 inhibitors in patients who have ASCVD, baseline LDL-C ≥190 mg/dL, and insufficient reduction in LDL-C (ie, reduction is <50%) with statin treatment.61 PCSK9 inhibitors are discussed in greater detail in the second article of this supplement.
Current Guidelines for the Management of Cholesterol
Numerous guidelines provide recommendations for the treatment of hyperlipidemia as well as FH. The 2013 ACC/AHA Guideline for the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults includes 4 main groups of patients for whom statin therapy could reduce the risk of ASCVD, along with recommendations for the intensity of statin therapy (Table 1 3).3
The ACC/AHA differs from the US Preventive Services Task Force (USPSTF) with regard to levels of statin intensity recommended. The USPSTF (Table 2169) recommends the use of low-to-moderate intensity statins in patients with a 10-year risk of ASCVD ≥10%, but for adult patients with a 10-year ASCVD risk between 7.5% and 10%, a low-to-moderate intensity statin is an option to consider.169
In contrast to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, which recommend a treat-to-target approach, the 2013 ACC/AHA guidelines endorse a tiered approach based on the average percentage by which a specific statin can reduce LDL-C.3,117 Statin regimens that can reduce LDL-C ≥50% are considered high-intensity therapies, while those statins that reduce LDL-C by 30% to <50% are considered moderate intensity, and those statins that reduce LDL-C ≤30% are considered low intensity.
High-intensity statin therapy is recommended in patients with FH by the ACC/AHA as well as by the Canadian Cardiovascular Society (CCS) and the European Atherosclerosis Society (EAS).47,61,170 Moderate-intensity therapy is recommended in patients who cannot tolerate high-intensity treatment. All guidelines for the treatment of FH recommend initiating treatment as soon as possible. In addition to statins, ezetimibe and PCSK9 inhibitors are recommended in patients who have an insufficient response to statins.3,61 While the CCS and EAS recommend the incorporation of bile acid sequestrants in patients with FH in need of further LDL-C reductions, the ACC/AHA 2013 guideline only recommends the use of nonstatins that have been shown to improve cardiovascular outcomes in randomized clinical trials, such as ezetimibe. The ACC/AHA 2013 guideline does not recommend the addition of niacin to statins based on data from the HSP2-THRIVE and AIM-HIGH studies that demonstrated an improvement in surrogate markers (eg, lipid parameters), but failed to show an increased benefit in cardiovascular outcomes.128,129 Similarly, the ACCORD study failed to show a benefit on ASCVD outcomes of adding fenofibrate to moderate-intensity statins, despite improvement in lipid parameters.171 Thus, the ACC/AHA 2013 guideline does not recommend the addition of fenofibrate to statin therapy. In 2015, the AHA and ACC made additional recommendations for the sequencing of treatment for FH with the addition of adjunctive therapies if patients do not reach LDL-C levels after 3 months of treatment (Figure172).61,172 Finally, the EAS guidelines recommend that LDL apheresis in combination with statins be initiated in patients with HoFH as early as 5 years of age and no later than 8 years of age in pediatric patients.12 In addition, lomitapide and mipomersen can be considered as adjunctive treatments for these patients who do not achieve the recommended LDL cholesterol targets and remain at high cardiovascular risk.
The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) 2017 lipid guidelines created a new patient population category deemed as “extreme risk” that would include individuals who have 1) “progressive ASCVD, including unstable angina, that persists after achieving an LDL-C <70 mg/dL,” 2) “established clinical cardiovascular disease in individuals with diabetes, stage III or IV chronic kidney disease (CKD), and/or HeFH,” and/or 3) “a history of premature ASCVD (males <55 years, females aged <65 years).”5 The treatment goals for individuals in this category are: LDL-C <55 mg/dL; non-HDL-C <80 mg/dL; and apo B <70 mg/dL.5 Regarding PCSK9 inhibitors, the AACE/ACE guidelines suggest their use in 2 patient groups: 1) patients with FH as combination therapy with statins, 2) patients with clinical CVD who do not attain LDL-C/non-HDL-C goals with maximally tolerated statin treatment. In the latter patient population, PCSK9 inhibitor monotherapy should only be considered in patients who are statin intolerant.5 PCSK9 inhibitors are also recommended in combination with statins in patients with FH to lower LDL-C levels.5
Recent changes to treatment recommendations are providing greater guidance for the management of hyperlipidemia, which includes a treat-to-target approach as well as using therapies based on the expected response. Although statins are the mainstay front-line treatment for hyperlipidemia, many patients, especially those with FH, do not achieve optimal LDL-C goals, thus requiring additional treatment. Statin therapy can be complicated by AEs (eg, myalgias) and rare but life-threatening rhabdomyolysis. These issues in treatment provide an opportunity to consider the use of PCSK9 inhibitors for patients who are nonadherent to statins, individuals that are statin intolerant, or those who are statin resistant.
Author affiliation: Associate Professor, Midwestern University College of Pharmacy, Pharmacy Practice Department, Glendale, AZ.
Funding source: This activity is supported by an education grant from Amgen, Inc.
Author disclosure: Dr Karr has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and supervision.
Address correspondence to: email@example.com.
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-e360. doi: 10.1161/CIR.0000000000000350.
2. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202-2207. doi: 10.1161/circulationaha.111.042523.
3. 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. J Am Coll Cardiol. 2014;63(25):2889-2934. doi: 10.1016/j.jacc.2013.11.002.
4. 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):129-169. doi: 10.1016/j.jacl.2015.02.003.
5. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(suppl 2):1-87. doi: 10.4158/EP171764.APPGL.
6. Cooney MT, Dudina A, De Bacquer D, et al. HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk. Atherosclerosis. 2009;206(2):611-616. doi: 10.1016/j.atherosclerosis.2009.02.041.
7. Centers for Disease Control and Prevention (CDC). Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol—United States, 1999-2002 and 2005-2008. MMWR Morb Mortal Wkly Rep. 2011;60(4):109-114.
8. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806. doi: 10.1001/jama.2014.732.
9. ACC/AHA. ACC/AHA ASCVD Risk Calculator website. www.cvriskcalculator.com. Published 2016. Accessed May 23, 2017.
10. Krähenbühl S, Pavik-Mezzour I, von Eckardstein A. Unmet needs in LDL-C lowering: when statins won’t do! Drugs. 2016;76(12):1175-1190. doi: 10.1007/s40265-016-0613-0.
11. Vogt A. The genetics of familial hypercholesterolemia and emerging therapies. Appl Clin Genet. 2015;8:27-36. doi: 10.2147/TACG.S44315.
12. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146-2157. doi: 10.1093/eurheartj/ehu274.
13. Ito MK, Watts GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs. 2015;75(15):1715-1724. doi: 10.1007/s40265-015-0466-y.
14. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype—phenotype relationship, and clinical outcome. Eur Heart J. 2015;36(9):560-565. doi: 10.1093/eurheartj/ehu058.
15. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490. doi: 10.1093/eurheartj/eht273.
16. Khera AV, Won HH, Peloso GM, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578-2589. doi: 10.1016/j.jacc.2016.03.520.
17. Perak AM, Ning H, de Ferranti SD, Gooding HC, Wilkins JT, Lloyd-Jones DM. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation. 2016;134(1):9-19. doi: 10.1161/circulationaha.116.022335.
18. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES) clinical perspective. Circulation. 2016;133(11):1067-1072. doi: 10.1161/CIRCULATIONAHA.115.018791.
19. Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8(1):18-28. doi: 10.1016/j.jacl.2013.11.002.
20. Youngblom E, Pariani M, Knowles JW. Familial hypercholesterolemia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2017..
21. Sjouke B, Hovingh GK, Kastelein JJP, Stefanutti C. Homozygous autosomal dominant hypercholesterolaemia. Curr Opin Lipidol. 2015;26(3):200-209. doi: 10.1097/MOL.0000000000000179.
22. Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis. 1997;130(1-2):191-197.
23. Black D, Davidson M, Koren M, et al. Cost effectiveness of treatment to National Cholesterol Education Panel (NCEP) targets with HMG-CoA reductase inhibitors. Trial design. Pharmacoeconomics. 1997;12(2 Pt 2):278-285.
24. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389. doi: 10.1016/S0140-6736(94)90566-5.
25. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. doi: 10.1016/S0140-6736(02)09327-3.
26. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4):220-228.
27. Insull W, Black D, Dujovne C, et al. Efficacy and safety of once-daily vs twice-daily dosing with fluvastatin, a synthetic reductase inhibitor, in primary hypercholesterolemia. Arch Intern Med. 1994;154(21):2449-2455.
28. Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol. 2002;89(3):268-275. doi: 10.1016/S0002-9149(01)02226-3.
29. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. doi: 10.1016/S0140-6736(10)61350-5.
30. Lipitor [package insert]. New York, NY: Pfizer, Inc; 2015.
31. Lescol/Lescol XL [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
32. Mevacor [package insert]. Morgantown, WV: Mylan Pharmaceuticals, Inc; 2014.
33. Pravachol [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
34. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2015.
35. Davidson M, McKenney J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I. Am J Cardiol. 1997;79(11):1475-1481.
36. Livalo [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, Inc; 2016.
37. Crestor [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2016.
38. Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation. 2012;126(18):e282-284. doi: 10.1161/circulationaha112.122135.
39. Skoumas J, Liontou C, Chrysohoou C, et al. Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia. Atherosclerosis. 2014;237(1):140-145. doi: 10.1016/j.atherosclerosis.2014.08.047.
40. Maki KC, Ridker PM, Brown WV, Grundy SM, Sattar N. The Diabetes Subpanel of the National Lipid Association Expert Panel. An assessment by the Statin Diabetes Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3):S17-S29. doi: 10.1016/j.jacl.2014.02.012.
41. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403-414. doi: 10.1007/s10557-005-5686-z.
42. Rosenbaum D, Dallongeville J, Sabouret P, Bruckert E. Discontinuation of statin therapy due to muscular side effects: a survey in real life. Nutr Metab Cardiovasc Dis. 2013;23(9):871-875. doi: 10.1016/j.numecd.2012.04.012.
43. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96-103. doi: 10.1161/CIRCULATIONAHA.112.136101.
44. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;1(1):1-23. doi: 10.5114/aoms.2015.49807.
45. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62-72. doi: 10.1056/NEJMra0801327.
46. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. The National Lipid Association’s Muscle Safety Expert Panel. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3):S58-S71. doi: 10.1016/j.jacl.2014.03.004.
47. Mancini GBJ, Baker S, Bergeron J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group update (2016). Can J Cardiol. 2016;32(7):S35-S65. doi: 10.1016/j.cjca.2016.01.003.
48. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA. 2007;297(2):177-186. doi: 10.1001/jama.297.2.177.
49. Bouchard MH, Dragomir A, Blais L, Bérard A, Pilon D, Perreault S. Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol. 2007;63(6):698-708. doi: 10.1111/j.1365-2125.2006.02828.x.
50. De Vera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78(4):684-698.
51. Cheetham TC, Niu F, Green K, et al. Primary nonadherence to statin medications in a managed care organization. J Manag Care Pharm. 2013;19(5):367-373. doi: 10.18553/jmcp.2013.19.5.367.
52. Fischer MA, Stedman MR, Lii J, et al. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010;25(4):284-290. doi: 10.1007/s11606-010-1253-9.
53. Raebel MA, Ellis JL, Carroll NM, et al. Characteristics of patients with primary non-adherence to medications for hypertension, diabetes, and lipid disorders. J Gen Intern Med. 2012;27(1):57-64. doi: 10.1007/s11606-011-1829-z.
54. Liberman JN, Hutchins DS, Popiel RG, Patel MH, Jan SA, Berger JE. Determinants of primary nonadherence in asthma-controller and dyslipidemia pharmacotherapy. Am J Pharm Benefits. 2010;2(2):111-118.
55. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 288(4):462-467.
56. Mann DM, Allegrante JP, Natarajan S, Halm EA, Charlson M. Predictors of adherence to statins for primary prevention. Cardiovasc Drugs Ther. 2007;21(4):311-316. doi: 10.1007/s10557-007-6040-4.
57. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44(9):1410-1421. doi: 10.1345/aph.1P150.
58. Chodick G, Shalev V, Gerber Y, et al. Long-term persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel. Clin Ther. 2008;30(11):2167-2179. doi: 10.1016/j.clinthera.2008.11.012.
59. Lemstra M, Blackburn D, Crawley A, Fung R. Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis. Can J Cardiol. 2012;28(5):574-580. doi: 10.1016/j.cjca.2012.05.007.
60. Spinler SA, Cziraky MJ, Willey VJ, et al. Frequency of attainment of low-density lipoprotein cholesterol and non—high-density lipoprotein cholesterol goals in cardiovascular clinical practice (from the National Cardiovascular Data Registry PINNACLE Registry). Am J Cardiol. 2015;116(4):547-553. doi: 10.1016/j.amjcard.2015.05.011.
61. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol. 2016;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519.
62. Ramalho de Oliveira D, Brummel AR, Miller DB. Medication therapy management: 10 years of experience in a large integrated health care system. J Manag Care Pharm. 2010;16(3):185-195. doi: 10.18553/jmcp.2010.16.3.185.
63. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29(2):253-260. doi: 10.1016/j.clinthera.2007.02.008.
64. Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiother Can. 2014;66(2):124-132. doi: 10.3138/ptc.2012-65.
65. Causevic-Ramosevac A, Semiz S. Drug interactions with statins. Acta Pharm. 2013;63(3):277-293. doi: 10.2478/acph-2013-0022.
66. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11. doi: 10.1016/j.phrs.2014.03.002.
67. Kellick KA, Bottorff M, Toth PP; The National Lipid Association’s Safety Task Force. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol. 2014;8(3):S30-S46. doi: 10.1016/j.jacl.2014.02.010.
68. Hu M, Tomlinson B. Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. Expert Opin Drug Metab Toxicol. 2014;10(1):51-65. doi: 10.1517/17425255.2014.851667.
69. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6(3):208-215. doi: 10.1016/j.jacl.2012.03.003.
70. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534. doi: 10.7326/0003-4819-158-7-201304020-00004.
71. El-Salem K, Ababneh B, Rudnicki S, et al. Prevalence and risk factors of muscle complications secondary to statins. Muscle Nerve. 2011;44(6):877-881. doi: 10.1002/mus.22205.
72. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C-60C. doi: 10.1016/j.amjcard.2005.12.010.
73. Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med. 2006;119(5):400-409. doi: 10.1016/j.amjmed.2006.02.007.
74. American College of Cardiology. ACC’s Statin Intolerance Tool. American College of Cardiology website. http://tools.acc.org/statinintolerance/. Published December 2016. Accessed May 18, 2017.
75. Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol. 2013;75(4):1118-1124. doi: 10.1111/j.1365-2125.2012.04403.x.
76. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy. J Am Coll Cardiol. 2013;61(2):148-152. doi: 10.1016/j.jacc.2012.09.042.
77. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556. doi: 10.1001/jama.2011.860.
78. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;347:f4356. doi: 10.1136/bmj.f4356.
79. Wong ND, Chuang J, Zhao Y, Rosenblit PD. Residual dyslipidemia according to low-density lipoprotein cholesterol, non—high-density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and Nutrition Examination Survey 2009-2010. J Clin Lipidol. 2015;9(4):525-532. doi: 10.1016/j.jacl.2015.05.003.
80. Della Badia LA, Elshourbagy NA, Mousa SA. Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol. Pharmacol Ther. 2016;164:183-194. doi: 10.1016/j.pharmthera.2016.04.011.
81. Braamskamp MJAM, Langslet G, McCrindle BW, et al. Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: results from the CHARON study. J Clin Lipidol. 2015;9(6):741-750. doi: 10.1016/j.jacl.2015.07.011.
82. Avis HJ, Hutten BA, Gagné C, et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll Cardiol. 2010;55(11):1121-1126. doi: 10.1016/j.jacc.2009.10.042.
83. Raal FJ, Pilcher GJ, Illingworth DR, et al. Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis. 1997;135(2):249-256.
84. Raal FJ, Pappu AS, Illingworth DR, et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis. 2000;150(2):421-428.
85. Marais AD, Raal FJ, Stein EA, et al. A dose-titration and comparative study of rosuvastatin and
atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis. 2008;
197(1):400-406. doi: 10.1016/j.atherosclerosis.2007.06.028.
86. Langslet G, Breazna A, Drogari E. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2016;10(5):1153-1162.e3. doi: 10.1016/j.jacl.2016.05.010.
87. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol. 2016;67(11):1278-1285. doi: 10.1016/j.jacc.2016.01.008.
88. Cholestyramine [package insert]. Maple Grove, MN: Upsher-Smith Laboratories, Inc; 2015.
89. Colestid [package insert]. New York, NY: Pfizer, Inc; 2014.
90. Welchol [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2014.
91. Lopid [package insert]. New York, NY: Pfizer, Inc; 2010.
92. Tricor [package insert]. Anngrove, Carrigtwohill Co. Cork, Ireland: Fournier Laboratories Ireland, Limited; 2013.
93. Niaspan [package insert]. North Chicago, IL: AbbVie, Inc; 2015.
94. Zetia [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2013.
95. Juxtapid [package insert]. Cambridge, MA: Aegerion Pharmaceuticals, Inc; 2016.
96. Kynamro [package insert]. Cambridge, MA: Genzyme Corporation; 2016.
97. Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US, LLC; 2015.
98. Repatha [package insert]. Thousand Oaks, CA: Amgen Inc; 2016.
99. Einarsson K, Ericsson S, Ewerth S, et al. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol. 1991;40(suppl 1):S53-S58.
100. Bays HE, Dujovne CA, McGovern ME, et al. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol. 2003;91(6):667-672.
101. Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (Cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159(16):1893-1900. doi: 10.1001/archinte.159.16.1893.
102. Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med. 2001;110(5):352-360.
103. Bays HE, Davidson M, Jones MR, Abby SL. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol. 2006;97(8):1198-1205. doi: 10.1016/j.amjcard.2005.11.039.
104. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(2):327-336.
105. Davidson MH, Toth P, Weiss S, et al. Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. Clin Cardiol. 2001;24(6):467-474.
106. Hunninghake DB, Mellies MJ, Goldberg AC, et al. Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing. Atherosclerosis. 1990;85(2-3):219-227.
107. McKenney J, Jones M, Abby S. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia. Curr Med Res Opin. 2005;21(9):1403-1412. doi: 10.1185/030079905X59157.
108. Davidson MH, Rooney M, Pollock E, Drucker J, Choy Y. Effect of colesevelam and niacin on low-density lipoprotein cholesterol and glycemic control in subjects with dyslipidemia and impaired fasting glucose. J Clin Lipidol. 2013;7(5):423-432. doi: 10.1016/j.jacl.2013.06.001.
109. Bays H, Rhyne J, Abby S, Lai Y-L, Jones M. Lipid-lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin. 2006;22(11):2191-2200. doi: 10.1185/030079906X148436.
110. Stein EA, Marais AD, Szamosi T, et al. Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia. J Pediatr. 2010;156(2):231-236.e3. doi: 10.1016/j.jpeds.2009.08.037.
111. Huijgen R, Abbink EJ, Bruckert E, et al. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther. 2010;32(4):615-625. doi: 10.1016/j.clinthera.2010.04.014.
112. Jialal I, Abby SL, Misir S, Nagendran S. Concomitant reduction in low-density lipoprotein cholesterol and glycated hemoglobin with colesevelam hydrochloride in patients with type 2 diabetes: a pooled analysis. Metab Syndr Relat Disord. 2009;7(3):255-258. doi: 10.1089/met.2009.0007.
113. Moore A, Phan BAP, Challender C, Williamson J, Marcovina S, Zhao XQ. Effects of adding extended-release niacin and colesevelam to statin therapy on lipid levels in subjects with atherosclerotic disease. J Clin Lipidol. 2007;1(6):620-625. doi: 10.1016/j.jacl.2007.09.001.
114. Brown W V, Dujovne CA, Farquhar JW, et al. Effects of fenofibrate on plasma lipids. Double-blind, multicenter study in patients with type IIA or IIB hyperlipidemia. Arteriosclerosis. 1996(6):670-678.
115. Knopp RH, Brown W V, Dujovne CA, et al. Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am J Med. 1987;83(5B):50-59.
116. Insua A, Massari F, Rodríguez Moncalvo JJ, Rubén Zanchetta J, Insua AM. Fenofibrate or gemfibrozil for treatment of types IIa and IIb primary hyperlipoproteinemia: a randomized, double-blind, crossover study. Endocr Pract. 2002;8(2):96-101. doi: 10.4158/EP.8.2.96.
117. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
118. Farnier M, Ducobu J, Bryniarski L. Long-term safety and efficacy of fenofibrate/pravastatin combination therapy in high risk patients with mixed hyperlipidemia not controlled by pravastatin monotherapy. Curr Med Res Opin. 2011;27(11):2165-2173. doi: 10.1185/03007995.2011.626398.
119. Roth EM, McKenney JM, Kelly MT, et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs. 2010;10(3):175-186. doi: 10.2165/11533430-000000000-00000.
120. Athyros VG, Papageorgiou AA, Athyrou V V, Demitriadis DS, Pehlivanidis AN, Kontopoulos AG. Atorvastatin versus four statin-fibrate combinations in patients with familial combined hyperlipidaemia. J Cardiovasc Risk. 2002;9(1):33-39.
121. Enger C, Gately R, Ming EE, Niemcryk SJ, Williams L, McAfee AT. Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J Cardiol. 2010;106(11):1594-1601. doi: 10.1016/j.amjcard.2010.07.041.
122. Amend KL, Landon J, Thyagarajan V, Niemcryk S, McAfee A. Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population. Ann Pharmacother. 2011;45(10):1230-1239. doi: 10.1345/aph.1Q110.
123. Probstfield JL, Hunninghake DB. Nicotinic acid as a lipoprotein-altering agent. Therapy directed by the primary physician. Arch Intern Med. 1994;154(14):1557-1559.
124. Insull W, Basile JN, Vo AN, Jiang P, Thakkar R, Padley RJ. Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study. J Clin Lipidol. 2009;3(2):109-118. doi: 10.1016/j.jacl.2009.02.009.
125. Airan-Javia SL, Wolf RL, Wolfe ML, Tadesse M, Mohler E, Reilly MP. Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy. Am Heart J. 2009;157(4):687.e1-687.e8. doi: 10.1016/j.ahj.2009.01.001.
126. Ballantyne CM, Davidson MH, McKenney JM, Keller LH, Bajorunas DR, Karas RH. Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study. J Clin Lipidol. 2008;2(2):79-90. doi: 10.1016/j.jacl.2008.02.004.
127. Chen F, Maccubbin D, Yan L, et al. Lipid-altering efficacy and safety profile of co-administered extended release niacin/laropiprant and simvastatin versus atorvastatin in patients with mixed hyperlipidemia. Int J Cardiol. 2013;167(1):225-231. doi: 10.1016/j.ijcard.2011.12.103.
128. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267. doi: 10.1056/NEJMoa1107579.
129. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212. doi: 10.1056/NEJMoa1300955.
130. Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 2008;101(5):625-630. doi: 10.1016/j.amjcard.2007.10.023.
131. Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2008;62(12):1959-1970. doi: 10.1111/j.1742-1241.2008.01938.x.
132. McKenney J, Ballantyne CM, Feldman TA, et al. LDL-C goal attainment with ezetimibe plus simvastatin coadministration vs atorvastatin or simvastatin monotherapy in patients at high risk of CHD. MedGenMed. 2005;7(3):3.
133. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107(19):2409-2415. doi: 10.1161/01.CIR.0000068312.21969.C8.
134. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study. Am Heart J. 2005;149(3):464-473. doi: 10.1016/j.ahj.2004.11.023.
135. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40(12):2125-2134.
136. Kerzner B, Corbelli J, Sharp S, et al. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol. 2003;91(4):418-424.
137. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2004;79(5):620-629. doi: 10.1016/S0025-6196(11)62283-0.
138. Masana L, Mata P, Gagné C, et al. Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study. Clin Ther. 2005;27(2):174-184. doi: 10.1016/j.clinthera.2005.02.011.
139. Melani L, Mills R, Hassman D, et al. Efficacy and safety of ezetimibe coadministered with
pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J. 2003;24(8):717-728.
140. Robinson JG, Ballantyne CM, Grundy SM, et al. Lipid-altering efficacy and safety of ezetimibe/
simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study). Am J Cardiol. 2009;103(12):1694-1702. doi: 10.1016/j.amjcard.2009.05.003.
141. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to
simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132(13):1224-1233. doi: 10.1161/CIRCULATIONAHA.115.018381.
142. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. doi: 10.1056/NEJMoa1410489.
143. Feldman T, Koren M, Insull W, et al. Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am J Cardiol. 2004;93(12):1481-1486. doi: 10.1016/j.amjcard.2004.02.059.
144. Gagné C, Gaudet D, Bruckert E; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105(21):2469-2475.
145. Stein E, Stender S, Mata P, et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004;148(3):447-455. doi: 10.1016/j.ahj.2004.03.052.
146. van der Graaf A, Cuffie-Jackson C, Vissers MN, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008;52(17):1421-1429. doi: 10.1016/j.jacc.2008.09.002.
147. Foody JM, Brown WV, Zieve F, et al. Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults ≥65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study). Am J Cardiol. 2010;106(9):1255-1263. doi: 10.1016/j.amjcard.2010.06.051.
148. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-46. doi: 10.1016/S0140-6736(12)61731-0.
149. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998-1006. doi: 10.1016/S0140-6736(10)60284-X.
150. Akdim F, Stroes ESG, Sijbrands EJG, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55(15):1611-1618. doi: 10.1016/j.jacc.2009.11.069.
151. McGowan MP, Tardif JC, Ceska R, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006.
152. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126(19):2283-2292. doi: 10.1161/CIRCULATIONAHA.112.104125.
153. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J. 2015;36(9):566-575. doi: 10.1093/eurheartj/eht549.
154. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33(9):1142-1149. doi: 10.1093/eurheartj/ehs023.
155. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62(23):2178-2184. doi: 10.1016/j.jacc.2013.07.081.
156. Ginsberg HN, Rader DJ, Raal FJ, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dL or higher. Cardiovasc Drugs Ther. 2016;30(5):473-483. doi: 10.1007/s10557-016-6685-y.
157. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769. doi: 10.1016/j.jacl.2015.08.006.
158. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):ehv370. doi: 10.1093/eurheartj/ehv370.
159. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi: 10.1056/NEJMoa1501031.
160. 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):1186-1194. doi: 10.1093/eurheartj/ehv028.
161. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-915.e13. doi: 10.1016/j.ahj.2015.03.004.
162. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin Endocrinol Metab. 2015;100(8):3140-3148. doi: 10.1210/jc.2015-1520.
163. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138-146. doi: 10.1016/j.atherosclerosis.2015.11.010.
164. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016;315(15):1580-1590. doi: 10.1001/jama.2016.3608.
165. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350. doi: 10.1016/S0140-6736(14)61374-X.
166. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340. doi: 10.1016/S0140-6736(14)61399-4.
167. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548. doi: 10.1016/j.jacc.2014.03.019.
168. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1882. doi: 10.1001/jama.2014.4030.
169. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;316(19):1997. doi: 10.1001/jama.2016.15450.
170. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. doi: 10.1093/eurheartj/ehw272.
171. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574. doi: 10.1056/NEJMoa1001282.
172. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132(22):2167-2192. doi: 10.1161/CIR.0000000000000297.