INTRODUCTION —
Familial hypercholesterolemia (FH) is the most common autosomal dominant genetic disease. The clinical syndrome (phenotype) is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and a propensity to early-onset atherosclerotic cardiovascular disease (ASCVD). In general, homozygotes manifest the disease at a much earlier age than heterozygotes, and the disease is more severe. This topic will focus on the treatment of FH in adults. An overview of FH in adults, including how to establish the diagnosis, as well as the management of FH in children and adolescents are discussed elsewhere:
●(See "Familial hypercholesterolemia in adults: Overview".)
●(See "Familial hypercholesterolemia in children", section on 'Management'.)
GENERAL PREVENTIVE MEASURES —
All patients with FH should receive the general preventive measures described below.
●Lifestyle changes – All patients with elevated LDL-C should be counseled on lifestyle changes that may decrease LDL-C levels. This counseling should include dietary modification (eg, reduced intake of saturated fat), physical activity, and weight loss in obese individuals. Most patients benefit from referral to a dietitian for detailed nutritional counseling. (See "Healthy diet in adults" and "Overview of primary prevention of cardiovascular disease in adults", section on 'Identifying and addressing key risk factors'.)
●Aspirin – Patients who have FH and clinically evident atherosclerotic cardiovascular disease (ASCVD) should receive aspirin 75 to 100 mg daily to reduce the risk of cardiovascular events, similar to patients in the general population who have ASCVD. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
Aspirin may be appropriate for patients with FH without known ASCVD, especially for those with uncontrolled LDL-C, due to their high risk of cardiovascular events. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Our approach'.)
●Patient education – Patients with known or suspected FH should be educated about the nature of the disease, including the potential for early ASCVD events.
WHEN TO REFER TO A LIPID SPECIALIST —
The following patients should be referred to clinicians who specialize in the management of lipid disorders:
●Adult patients with a confirmed or suspected diagnosis of homozygous FH. Most of these patients are already under a lipid specialist’s care because the diagnosis of homozygous FH is usually made during childhood.
●Certain adult patients with a confirmed or suspected diagnosis of heterozygous FH, including the following:
•Those who have not achieved their LDL-C goal with commonly used lipid-lowering agents. (See 'Goals of therapy' below.)
•Those who have signs or symptoms suggestive of atherosclerotic cardiovascular disease (ASCVD) or aortic stenosis, both of which are more prevalent in individuals with uncontrolled hypercholesterolemia.
APPROACH TO PHARMACOLOGIC THERAPY —
Our approach to the pharmacologic treatment of FH in adults is described in this section.
Goals of therapy — The goal of pharmacologic therapy for patients with FH is to lower the LDL-C to target levels to reduce the risk of cardiovascular disease and mortality. An individual patient’s LDL-C goal depends on their risk for atherosclerotic cardiovascular disease (ASCVD). These goals are similar to those in published guidelines [1,2].
●Very high risk – For patients with FH who are at very high risk for ASCVD events (ie, those with clinically evident ASCVD), we target a goal LDL-C of ≤55 mg/dL (1.4 mmol/L).
●High risk – For patients with FH who are at high risk for ASCVD events (ie, those with subclinical ASCVD or diabetes mellitus), we target a goal LDL-C of ≤70 mg/dL (1.8 mmol/L).
●Low risk – For all other patients with FH, experts have different approaches; some use a goal LDL-C of ≤100 mg/dL (2.6 mmol/L), while others choose a goal of ≤70 mg/dL (1.8 mmol/L) or ≤100 mg/dL (2.6 mmol/L) depending on specific patient characteristics. Examples of patients who might merit more intensive treatment include:
•A patient in whom subclinical ASCVD has not been excluded.
•A middle-aged patient who has had untreated FH for many years.
•A young, female patient who, while not currently trying to conceive, may in the future need to discontinue lipid-lowering therapy for several years (during conception attempts, pregnancies, and breastfeeding). (See 'Pregnant patients' below.)
The LDL-C goal may be difficult to meet because the mechanisms of action of commonly used drugs (eg, statins, PCSK9 inhibitors) depend on the activity of the LDL receptor, which is reduced or nonfunctional in these patients. This is particularly true for patients with homozygous FH because of the magnitude of the LDL-C elevation, which can be as high as 500 mg/dL (13 mmol/L). (See "Statins: Actions, side effects, and administration", section on 'Mechanism of action'.)
Intensive LDL-C lowering in individuals with FH decreases the progression of angiographically demonstrated coronary artery disease [3], and reduces cardiovascular disease events (myocardial infarction) [4], coronary artery disease mortality [5], and all-cause mortality [3-6]. The magnitude of benefit has varied in these studies due to differences in populations, endpoints, and intensity and duration of treatment. While all studies on the impact of lipid-lowering therapy on mortality in patients with FH have been observational, the results are consistent with the findings of randomized trials (usually with statins) that enrolled many individuals without FH. In the aggregate, these secondary prevention studies found a reduction in the risk of cardiovascular death and myocardial infarction. (See "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Patients with homozygous familial hypercholesterolemia — Most patients with homozygous FH receive a diagnosis in childhood and should be treated rigorously with lipid-lowering therapy at the time of diagnosis. Such patients are generally managed by a pediatric lipid specialist, as discussed separately. (See "Familial hypercholesterolemia in children", section on 'Management of HoFH'.)
In the rare case of an adult with suspected homozygous FH (eg, a young adult with an atherosclerotic cardiovascular disease [ASCVD] event and an extremely elevated LDL-C), we typically start a high-potency statin (eg, rosuvastatin or atorvastatin) and refer the patient to an adult lipid specialist for genetic testing and further management. Patients with homozygous FH generally require additional lipid-lowering therapies to reduce their LDL-C; however, the effectiveness of different agents depends in part on the patient’s genetic diagnosis. As an example, studies have shown that PCSK9 inhibitors lower LDL-C by more than 50 percent in patients with heterozygous FH [7] but only 30 percent in patients with homozygous FH [8-12]. Thus, treatment decisions are best made by a lipid specialist with clinical expertise in the management of patients with FH. (See 'When to refer to a lipid specialist' above.)
Patients with heterozygous familial hypercholesterolemia — Our approach to pharmacologic therapy in patients with heterozygous FH is discussed below (algorithm 1).
Initial therapy (statins) — For most nonpregnant adults with heterozygous FH, we recommend initial therapy with a high-potency statin rather than a low-potency statin. We typically use rosuvastatin (40 mg daily) or atorvastatin (80 mg daily) because of their superior lipid-lowering efficacy over other statins in randomized trials including patients with FH [13-15]. Observational studies of patients with heterozygous FH have demonstrated a reduction in cardiovascular disease events and mortality with statin therapy [5]. The treatment of pregnant patients with FH is discussed elsewhere in this topic. (See 'Pregnant patients' below and "Statins: Actions, side effects, and administration".)
After 6 to 12 weeks on a high-potency statin, we remeasure the LDL-C. In patients with heterozygous FH, the LDL-C may decrease by up to 60 percent [15].
●If the LDL-C has decreased by at least 50 percent, our clinical approach depends upon whether the patient has achieved their goal LDL-C:
•If the patient’s LDL-C is at their goal, we continue the statin and routine LDL-C monitoring.
•If the patient’s LDL-C is above their goal, we proceed to add a second-line lipid-lowering medication. (See 'Second-line therapies (ezetimibe/PCSK9 inhibitors)' below.)
●If the LDL-C has not decreased by at least 50 percent, we assess the patient’s adherence to statin therapy.
•If the patient has not been adherent to statin therapy, we try to understand the reasons for nonadherence and tailor our approach to the individual patient. As an example, if nonadherence is primarily due to medication side effects (eg, myalgias), options include restarting the statin at a lower dose or switching to a different high-potency statin. If the patient cannot tolerate either statin, we discontinue the medication and proceed to a second-line therapy. (See 'Second-line therapies (ezetimibe/PCSK9 inhibitors)' below.)
•If the patient has been taking the statin as prescribed, options include adding a second-line therapy or trying the other high-potency statin since individual patients may respond differently to a given statin. If the patient switches statins, we repeat the LDL-C in 6 to 12 weeks. If the LDL-C is higher, we switch them back to the initial statin; otherwise, we continue the new statin. If the patient’s LDL-C remains above their goal, we proceed to add a second-line lipid-lowering medication. (See 'Second-line therapies (ezetimibe/PCSK9 inhibitors)' below.)
Second-line therapies (ezetimibe/PCSK9 inhibitors) — For patients with heterozygous FH whose LDL-C remains above their goal despite the use of a high-potency statin, or who are unable to tolerate a high-potency statin, preferred second-line therapies include ezetimibe and a PCSK9 inhibitor.
Our approach to selecting a second-line medication depends upon how far the patient’s LDL-C is from their goal. LDL-C goals are discussed above. (See 'Goals of therapy' above.)
●For patients whose LDL-C is above their goal by ≤25 percent, we suggest adding ezetimibe (10 mg daily) rather than a PCSK9 inhibitor. Such patients are likely to achieve their goal LDL-C with the addition of ezetimibe. In a trial of 720 patients with FH who were taking simvastatin, ezetimibe lowered the LDL-C by 27 percent compared with placebo [16]. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)
LDL-C should be measured 4 to 12 weeks after the addition of ezetimibe. If the LDL-C is at goal, we continue the patient’s lipid-lowering regimen and continue routine monitoring of LDL-C. If the LDL-C is above the goal, we add a PCSK9 inhibitor, as discussed in the bullet below. If the LDL-C remains above the goal following the addition of a PCSK9 inhibitor, additional therapy for refractory hypercholesterolemia may be warranted. (See 'Refractory hypercholesterolemia' below.)
●For patients whose LDL-C is above their goal by >25 percent, we suggest adding a PCSK9 inhibitor rather than ezetimibe. In such patients, the addition of a PCSK9 inhibitor is more likely to achieve the goal LDL-C than the addition of ezetimibe. However, ezetimibe may be preferred for certain patients, such as those who prefer oral rather than subcutaneous medication and those whose insurers require a trial of ezetimibe first.
If a PCSK9 inhibitor is chosen, we prescribe either a PCSK9 monoclonal antibody (eg, alirocumab, evolocumab) or inclisiran, a small interfering RNA that inhibits hepatic synthesis of PCSK9. The choice of medication is impacted by availability, cost, and patient preference. Inclisiran may be preferred by patients because it requires less frequent injections than alirocumab or evolocumab. Dosing of alirocumab, evolocumab, and inclisiran, all of which are given subcutaneously, is discussed elsewhere. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Dosing in adults' and "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Small interfering RNA (inclisiran)'.)
LDL-C should be checked 6 to 12 weeks after the addition of a PCSK9 inhibitor. The test should be performed one to two days before a dose of the drug is due (ie, at the nadir of the drug’s effect). If the LDL-C is at goal, we continue the patient’s lipid-lowering regimen and routine monitoring of LDL-C. If the LDL-C remains above goal, adding ezetimibe (as discussed in the bullet above) or adding additional therapy for refractory hypercholesterolemia may be warranted. (See 'Refractory hypercholesterolemia' below.)
Studies have demonstrated that PCSK9 monoclonal antibodies safely lower LDL-C by more than 50 percent in patients with heterozygous FH [7]. In a double-blind study of 62 patients with heterozygous FH receiving regular LDL apheresis, 63 percent of patients on alirocumab were able to discontinue apheresis treatments [17]. Inclisiran has been shown to reduce LDL-C by 40 percent in heterozygous FH [18]. While there are no trials demonstrating improved clinical outcomes with PCSK9 inhibitors in patients with FH, an open-label trial of 104 patients with FH who did not have clinical ASCVD found reduced coronary plaque burden and improved plaque stability on coronary computed tomographic angiography with the PCSK9 inhibitor alirocumab [19].
Refractory hypercholesterolemia — Patients with FH whose LDL-C remains above their goal despite treatment with first- and second-line therapies are considered to have refractory hypercholesterolemia. These patients should be referred to a lipid specialist if they are not already under a specialist’s care. We have a conversation with the patient about their dietary habits and may refer them to a dietitian for counseling. In addition, we evaluate the patient for secondary causes of hypercholesterolemia (eg, hypothyroidism, nephrotic syndrome). (See "Secondary causes of dyslipidemia".)
When deciding whether to add another therapy, we consider the patient’s overall risk of cardiovascular disease and the magnitude of the difference between their LDL-C and the goal LDL-C. For a patient at low risk whose LDL-C is only slightly higher (eg, 10 to 20 percent) than their goal, for example, it might be reasonable to intensify lifestyle changes rather than introducing an additional therapy. However, for a patient at very high risk whose LDL-C is much higher (eg, 90 percent) than their goal, we would treat with additional therapy to further lower LDL-C. The choice of additional therapy should be individualized based on availability, cost, and patient preference. Possible therapies for refractory disease include the following:
●Colesevelam – Colesevelam is a bile acid sequestrant. It is initially dosed as one 625 mg tablet with breakfast and gradually increased to two tablets three times daily with food as tolerated. Colesevelam was shown to reduce LDL-C by 19 percent in patients with FH who are already taking a statin and ezetimibe [20]. The drug may be a good choice for patients with diabetes because it has also been shown to improve glycemic control [21]. Colesevelam may cause gastrointestinal side effects, especially at high doses.
●Bempedoic acid – Bempedoic acid inhibits an enzyme upstream of 3-hydroxy-3-methylglutarly-CoA reductase in the cholesterol biosynthesis pathway. It is dosed at 180 mg daily. Bempedoic acid was shown to reduce LDL-C in patients with heterozygous FH who were already taking a statin by 16 to 18 percent [22-24]. Details are discussed elsewhere. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bempedoic acid'.)
●Evinacumab – Evinacumab is a monoclonal antibody to angiopoietin-like 3 (ANGPTL3) that lowers LDL-C by an LDL receptor-independent mechanism. The medication is given as a 15 mg/kg intravenous (IV) infusion every four weeks. Evinacumab has been demonstrated to reduce LDL-C by 47 percent in patients with homozygous FH who are already on other lipid-lowering agents [25]. While evinacumab has also been shown to reduce LDL-C by 49 to 56 percent in patients with heterozygous FH, the medication is often difficult to obtain for patients with this diagnosis [26].
●LDL apheresis – LDL apheresis is the extracorporeal removal of circulating apo B-containing lipoproteins. The procedure is performed weekly or biweekly. LDL apheresis lowers LDL-C acutely by 50 to 76 percent [27]. There are few centers that offer LDL apheresis, and the cost (2000 to 4000 United States dollars per session) is often prohibitive. Details are discussed elsewhere. (See "Treatment of drug-resistant hypercholesterolemia", section on 'LDL apheresis'.)
●Lomitapide – Lomitapide is an option only for patients with homozygous FH. The drug is an inhibitor of microsomal triglyceride transfer protein, which transfers triglycerides onto apolipoprotein B as part of the assembly of very low-density lipoprotein within the liver. We do not use this medication in patients with liver disease because it carries a black box warning due to the potential for liver toxicity. Details regarding eligibility, initiation, and monitoring are found elsewhere. (See "Treatment of drug-resistant hypercholesterolemia", section on 'Lomitapide'.)
●Other options – For rare patients who have exhausted other options, liver transplantation and partial ileal bypass surgery may be considered. These therapies are discussed separately. (See "Treatment of drug-resistant hypercholesterolemia", section on 'Liver transplantation' and "Treatment of drug-resistant hypercholesterolemia", section on 'Partial ileal bypass surgery'.)
PREGNANT PATIENTS —
All patients with FH who are interested in becoming pregnant should receive the following counseling and management:
●Maternal and fetal outcomes – Patients with FH should be informed that maternal and fetal outcomes in heterozygous FH are comparable to those of the general population [28], while outcomes in homozygous FH have not been studied.
●Medication management – For most patients with FH, we stop all lipid-lowering medications 6 to 12 weeks before they attempt to conceive. Statins are generally contraindicated during pregnancy due to the risk of fetal toxicity, and most other lipid-lowering agents have not been well studied during pregnancy. Patients should remain off these medications for the duration of pregnancy and breastfeeding. We would consider continuing a statin only for the rare patient with both homozygous FH and clinical cardiovascular disease, and only after a thorough discussion with the patient about the risks and benefits of statin therapy during pregnancy. LDL apheresis is a possible treatment option for pregnant patients with severe hypercholesterolemia, especially those with a history of cardiovascular events. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)
●Risk of uncontrolled hypercholesterolemia – Patients should understand that they will have uncontrolled hypercholesterolemia after stopping lipid-lowering therapies. While the risk of an atherosclerotic cardiovascular event during pregnancy is low, untreated hypercholesterolemia increases the long-term risk of developing cardiovascular disease. Patients should consider attempting to become pregnant at a younger age, when conception is easier, to minimize their time off lipid-lowering medications.
●Screening for coronary disease – We screen patients with homozygous FH who are planning to become pregnant for possible coronary artery disease, although there are no data to support this approach. For those with heterozygous FH, we screen if they are over age 40. For patients who have physical examination findings suggestive of aortic stenosis, we perform an echocardiogram to screen for asymptomatic aortic stenosis. Abnormal test results may warrant further workup and treatment before conception. (See "Screening for coronary heart disease", section on 'Screening tests'.)
●Breastfeeding – We do not use lipid-lowering therapies for most patients who are breastfeeding, with the possible exception of colesevelam. We usually counsel against prolonged breastfeeding so that patients can resume their lipid-lowering therapy as soon as possible.
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Familial hypercholesterolemia (The Basics)")
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary prevention of cardiovascular disease" and "Society guideline links: Lipid disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●General principles
•All patients with elevated low-density lipoprotein cholesterol (LDL-C) should be counseled on lifestyle changes. We recommend aspirin (75 to 100 mg daily) for patients who have familial hypercholesterolemia (FH) and clinical atherosclerotic cardiovascular disease (ASCVD) to reduce the risk of cardiovascular events. Aspirin may be appropriate for FH patients without known ASCVD because of their high risk of cardiovascular events. (See 'General preventive measures' above.)
•Adult patients with homozygous FH should be referred to a lipid specialist with expertise in FH. Adult patients with heterozygous FH who have not achieved their LDL-C goal with commonly used lipid-lowering agents or have evidence of cardiovascular disease should also be referred. (See 'When to refer to a lipid specialist' above.)
●Approach to pharmacologic therapy
•Goal of therapy – For patients at very high risk of cardiovascular events (ie, those with clinically apparent ASCVD), we target a goal LDL-C ≤55 mg/dL (1.4 mmol/L) (algorithm 1). For patients at high risk (ie, those with subclinical ASCVD or diabetes mellitus), we target a goal LDL-C ≤70 mg/dL (1.8 mmol/L). For patients at low risk, a goal LDL-C ≤100 mg/dL (2.6 mmol/L) is reasonable for most patients but more intensive therapy is sometimes appropriate due to the cumulative exposure to a high LDL-C level. (See 'Goals of therapy' above.)
•Initial drug therapy – For most nonpregnant adults with FH, we recommend initial therapy with a high-potency statin (rosuvastatin 40 mg daily or atorvastatin 80 mg daily) (Grade 1B). After 6 to 12 weeks, if the LDL-C has not dropped by at least 50 percent, we counsel the patient about medication nonadherence (if present), try the other high-potency statin, or proceed to add a second-line agent. (See 'Initial therapy (statins)' above.)
•Second-line drug therapy – For patients with heterozygous FH who do not achieve their LDL-C goal after 6 to 12 weeks on a high-potency statin, or who do not tolerate the statin, the choice of second-line medication depends on how far the patient’s LDL-C is from their goal. (See 'Second-line therapies (ezetimibe/PCSK9 inhibitors)' above.)
-For patients whose LDL-C exceeds their goal by ≤25 percent, we suggest adding ezetimibe (10 mg daily) (Grade 2C). If the LDL-C remains elevated on ezetimibe, we suggest adding a PCSK9 inhibitor (Grade 2C).
-For patients whose LDL-C exceeds their goal by >25 percent, we suggest adding a PCSK9 inhibitor (Grade 2C).
•Therapies for refractory hypercholesterolemia – If the LDL-C remains above goal after introducing ezetimibe or PCSK9 inhibitor, we evaluate the patient for secondary causes of hypercholesterolemia. Further treatment options include ezetimibe (if not already tried), colesevelam, bempedoic acid, evinacumab, LDL apheresis, lomitapide, liver transplantation, and partial ileal bypass surgery. (See 'Refractory hypercholesterolemia' above.)
●Pregnant patients – For most patients with FH, we stop all lipid-lowering medications 6 to 12 weeks before they attempt to conceive. Patients should remain off these medications for the duration of pregnancy and breastfeeding. In rare cases (eg, a patient with homozygous FH and ASCVD), a statin might be continued during pregnancy. LDL apheresis is a possible therapeutic option for pregnant patients with severe hypercholesterolemia, especially those with a history of cardiovascular events (See 'Pregnant patients' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff thanks Sarah D de Ferranti, MD, MPH, who contributed to earlier versions of this topic review.