Familial hypercholesterolemia in adults: Treatment

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. 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 primary goal of therapy in FH adults: to significantly lower LDL-C levels. Other issues regarding FH in adults are presented separately. (See "Familial hypercholesterolemia in adults: Overview".)

The management of children and adolescents with heterozygous or homozygous FH is discussed separately. (See "Familial hypercholesterolemia in children", section on 'Management'.)

REFERRAL TO A LIPID SPECIALIST — All patients with a diagnosis of homozygous familial hypercholesterolemia should be referred to a lipid specialist with particular expertise in the care of these individuals. For adult heterozygote patients who have not achieved their low density lipoprotein cholesterol goal (see 'Goal of therapy' below) on statin therapy, consideration should be given to referral.

RATIONALE FOR INTENSE LDL-C LOWERING — Intense low density lipoprotein cholesterol (LDL-C) lowering in individuals with heterozygous or homozygous familial hypercholesterolemia (FH) decreases progression of angiographically demonstrated coronary artery disease [1], and reduces cardiovascular disease events (myocardial infarction) [2], coronary heart disease mortality [3], and all-cause mortality [1-4]. The magnitude of benefit has varied in these studies due to differing populations, the end point chosen, as well as the intensity and duration of treatment. Reduction in combined end points of up to 50 percent have been found.

While all studies of the impact of therapy on mortality in FH patients 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 lowering of the risk for cardiovascular death and myocardial infarction. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Finally, at any level of untreated LDL-C, the prognosis for patients with heterozygous FH is worse than those without. (See "Familial hypercholesterolemia in adults: Overview", section on 'Prognosis'.)

GENERAL PREVENTIVE MEASURES — All patients with elevated low density lipoprotein cholesterol (LDL-C) should be counseled in lifestyle changes that may decrease LDL-C levels, as well as other cardiovascular risks. This counseling should include dietary modification, physical activity, and weight loss in obese individuals. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Lifestyle modifications' and "Overview of primary prevention of cardiovascular disease".)

Aspirin may be appropriate for many of these patients, as they are considered by most experts to be at high risk for a cardiovascular disease event. Specifically, we recommend aspirin for patients with clinical atherosclerotic cardiovascular disease, and men >55 years of age who have multiple coronary heart disease risk factors.

HOMOZYGOUS INDIVIDUALS — This section applies to adults with homozygous (HoFH). The management of HoFH in children is discussed separately. (See "Familial hypercholesterolemia in children", section on 'Management'.)

All adult patients with HoFH should receive care from a lipid expert, and many will benefit from the care of a cardiovascular specialist (see 'Referral to a lipid specialist' above). As the disease and its clinical consequences begin at birth, most patients will have been evaluated and treated in childhood. By the time they are under the care of adult physicians, many will have established cardiovascular disease. However, a few will be fortunate enough to be disease-free due to successful lipid-lowering treatment.

Goal of therapy — The broad goal of therapy is to lower the LDL-C with the therapies described below (in this section) as much as is practical (intensive lowering). "Practical" is determined by patient preference, cost, and availability of therapies. Setting a specific LDL-C target, while logical in other patients with elevated LDL-C, may not be helpful in this population.

HoFH patients often have untreated LDL-C of >500 mg/dL (>13 mmol/L). There is little agreement among experts on the specific LDL-C goal. Values between <50 mg/dL (1.3 mmol/L) and 135 mg/dL (3.5 mmol/L) have been articulated. However, values at the low end of this range may be difficult if not impossible to achieve even with multiple cholesterol-lowering drugs. This is due to the fact that they usually depend on the presence of the LDL receptor, which is absent or nearly absent in these patients, for their effect. (See "Statins: Actions, side effects, and administration", section on 'Mechanism of action'.)

Our approach — The treatment strategy for patients with HoFH will likely include a high-dose statin and may include ezetimibe, a PCSK9 inhibitor, LDL apheresis, or lomitapide.

●Statin – Based on their safety, ease of use, and potential for significant LDL-C lowering even in patients with HoFH, high-dose statin therapy is used in most individuals.

●Ezetimibe – Although ezetimibe has not been evaluated in this setting, we often add it to statin based on clinical experience.

●PCSK9 inhibitor – In many patients, we add a PCSK9 inhibitor to statin and ezetimibe. We specifically may use a PCSK9 inhibitor as an additional agent in patients who do not meet cholesterol treatment goals with maximally tolerated lipid-lowering therapies (eg, statins, ezetimibe) or as an alternative agent in patients who are intolerant of such therapies. We suggest that this therapy is guided by a lipid specialist. Multiple studies have demonstrated that this class of drug effectively and safely lowers LDL-C in individuals with homozygous FH as long as some LDL receptor function is present [5-9]. In these studies, LDL-C was lowered by about 30 percent. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

The 2020 ODYSSEY HoFH trial is the largest study of PCSK9 inhibitors in these patients [9]. In this study, 69 patients treated with conventional LDL-C-lowering therapy (usually statin and ezetimibe) were randomly assigned to alirocumab or placebo. Mean baseline LDL-C was 295 and 260 mg/dL in the two groups, respectively. LDL-C levels decreased by 26 percent after 12 weeks on active drug and increased by 8.6 percent in those on placebo (p<0.0001). The safety profile of alirocumab was comparable to that of placebo.

Although LDL-C lowering with PCSK9 inhibitor in the range of 30 percent is important and likely associated with an incremental decrease in the rate of adverse cardiovascular events, the LDL-C will remain significantly above the LDL-C goal, discussed above. (See 'Goal of therapy' above.)

●Additional therapies – After therapy with statin, ezetimibe, and a PCSK9 antibody, the LDL-C goal should be reevaluated and a determination made as to whether additional therapy should be added [4]. Many homozygous patients will require additional therapies to lower LDL-C, including LDL-C apheresis, liver transplantation, portocaval shunt, or lomitapide. Most of these do not require the presence of the LDL receptor. These uncommonly used therapies are generally prescribed by a lipid specialist. (See "Treatment of drug-resistant hypercholesterolemia", section on 'LDL apheresis' and "Treatment of drug-resistant hypercholesterolemia", section on 'Lomitapide'.)

Monoclonal antibodies to angiopoietin-like 3 (ANGPTL3) have been shown to reduce LDL-C by >50 percent. ANGPTL3 is a hormone produced by the liver and inhibits lipoprotein lipase, an enzyme that breaks down plasma triglycerides, and lowers LDL-C by an LDL receptor-mediated pathway. Evinacumab is one such ANGPTL3 monoclonal antibody. The drug is being used by some lipid experts in patients with HoFH. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Endogenous pathway of lipid metabolism'.)

In the ELIPSE HoFH trial, 65 patients with homozygous FH who were receiving stable lipid-lowering therapy (44 percent were receiving statin, ezetimibe, and a PCSK9 inhibitor) were randomly assigned in a 2:1 manner to an intravenous infusion of evinacumab or placebo every four weeks [10]. The diagnosis of HoFH was based on either genetic or clinical criteria. The mean baseline LDL-C was 255.1 mg/dL. At week 24, the primary outcome of the percent change from baseline in calculated LDL-C was a reduction of 47.1 percent in the evinacumab group and an increase of 1.9 percent in the placebo group (p<0.001). The absolute difference in LDL-C was -132.1 mg/dL, comparing evinacumab with placebo. The rate of adverse events was 66 and 81 percent in the two groups, respectively. Consistent with their mode of action, the results were independent of the degree of LDL-receptor function. Triglycerides and high-density lipoprotein-cholesterol were also significantly lowered. There were two serious adverse events in the evinacumab group: urosepsis and a suicide attempt.

HETEROZYGOUS INDIVIDUALS — The vast majority of adult patients with familial hypercholesterolemia (FH) encountered in clinical practice will be heterozygotes and will usually have an untreated low density lipoprotein cholesterol (LDL-C) ≥190 mg/dL (figure 1). We recommend intensive lipid lowering for virtually all patients diagnosed with heterozygous FH.

Numerous studies have found that these individuals often receive suboptimal treatment or no treatment. In a retrospective analysis of 2382 patients referred to the cardiac catheterization laboratory with LDL-C ≥130 mg/dL, severe FH, defined by any prior LDL-C ≥280 mg/dL, was identified in 54 patients [11]. LDL-C reduction ≥50 percent of the peak value was achieved in 56 percent, LDL-C <130 mg/dL in 32 percent, and LDL-C <100 mg/dL in 17 percent of patients. Treatment with high-intensity statins plus ezetimibe was prescribed for 67 percent, high-intensity statin alone in 24 percent, and other lipid-lowering therapies in 9 percent of patients. In the SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) that included 2732 patients with molecularly diagnosed FH, 46.8 percent were treated with maximal combination therapy (high-intensity statin plus ezetimibe), and 71.8 percent on maximal lipid-lowering therapy (treatment with an anticipated >50 percent reduction in LDL-C) [12]. Among patients treated with maximum lipid-lowering therapy, an LDL-C treatment target <100 mg/dL was achieved by only 11.2 percent of patients. The multivariable predictors of incident atherosclerotic cardiovascular disease (ASCVD) at five years were age ≥60 years (hazard ratio 2.92 [1.14 to 7.52 for ages 30 to 59 years], and 4.27 [1.60 to 11.48 for ages ≥60 years versus <30 years]), male sex (hazard ratio 2.01 [1.33 to 3.04]), history of ASCVD before enrollment (4.15 [2.55 to 6.75]), high blood pressure (1.99 [1.26 to 3.15]), obesity (2.67 [1.47 to 4.85]), active smoking (1.62 [1.08 to 2.44]), and LDL-C between 100 and 159 mg/dL (2.50 [0.60 to 10.53]) and ≥160 mg/dL (4.80 [1.15 to 20.01]) [13].

Our approach — We attempt to have a detailed discussion with each patient prior to initiating therapy. Similarly, it is important for the clinician and the patient to have an ongoing dialog. Prior to starting therapy, we teach the patient about the nature of the disease, including the potential for early atherosclerotic cardiovascular disease events. An explanation of the benefits and risks of therapy as well as the fact that there are factual gaps in our understanding of the disease is essential. The patient should be informed that these gaps prevent us from being able to make strong recommendations regarding the end point of therapy in some situations.

For heterozygous FH patients, the following steps (sequentially) are a reasonable approach (algorithm 1):

●Set LDL-C goal. (See 'Goal of therapy' below.)

●Initiate high-dose statin therapy. (See 'Initial drug therapy' below.)

●Measure LDL-C in 6 to 12 weeks. If the patient is not at LDL-C goal after statin, start ezetimibe 10 mg daily and repeat LDL-C in 6 to 12 weeks. If the patient remains above the goal, refer the patient to a lipid specialist for consideration of adding a PCSK9 inhibitor. (See 'Second-line therapy' below.)

●Some patients who do not achieve their LDL-C goal on statin, ezetimibe, and PCSK9 inhibitor are candidates for third line therapy, which may be recommended by a lipid specialist. This group of patients may include individuals at very high risk of a cardiovascular disease event. (See 'Third-line treatment' below.)

Goal of therapy — Most experts agree that intensive lowering of LDL-C is indicated for heterozygous FH patients. The rationale is presented above. (See 'Rationale for intense LDL-C lowering' above.)

We acknowledge that many patients will not be able to achieve their LDL-C goals for reasons presented below. One of the difficult tasks in the management of LDL-C for the clinician and his or her patient is the determination when the LDL-C is close enough to goal such that additional therapy will not be started.

In addition, some experts believe that there should be different goals for different risk FH patients. For example, the risk of a cardiovascular disease event is different for the following two patients with identical on-treatment LDL-C: someone without a history of cardiovascular disease and another individual with a recent myocardial infarction.

Achieving an intensive LDL-C goal may be difficult for many reasons, including the following:

●Among patients with FH, the pretreatment LDL-C is greatly variable, ranging from 190 mg/dL to greater than 500 mg/dL. If statin therapy consistently reduced LDL-C levels by 60 percent, post-statin LDL-C levels would range from 76 mg/dL to greater than 200 mg/dL. In reality, there is even greater variation since LDL-C response to statin therapy at the maximally tolerated dose ranges from 20 to 60 percent. Thus, it may be unrealistic for a patient whose starting LDL-C is 500 mg/dL to achieve an LDL-C of <70 mg/dL.

●Some therapies, such as PCSK9 inhibitors, are costly and may not be an option for some patients.

While not based on randomized trial evidence, we believe the following broad approach to goal setting is reasonable:

●The LDL-C goal should be individualized for each patient, given the above considerations.

●Based on the starting LDL-C, we consider a high intensity statin and ezetimibe as initial therapy for those high-risk patients who may benefit from >60 percent reduction in LDL-C. 

This LDL-C goal can be modified (higher or lower) based on the patient’s risk of future cardiovascular events. For very high-risk FH individuals, such as those with diabetes, multiple other cardiovascular disease risk factors, prior acute coronary syndrome, stages 3 or 4 chronic kidney disease, or atherosclerosis in multiple cardiovascular beds, we choose a more aggressive target of 55 mg/dL. Although there is no evidence to recommend this particular number, it has practical value in that it is easy to remember and is measurably lower than 70 mg/dL.

For patients felt to be at very low risk, an LDL-C goal of 100 mg/dL may be reasonable.

Our suggestions for therapies to achieve these goals are discussed directly below. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Identifying patients at high risk'.)

Initial drug therapy — Most experts agree that all FH patients should receive maximally tolerated statin therapy and that a statin should be the initial drug therapy. In initial studies, FH heterozygotes were typically treated with multidrug regimens, which included less potent statins. Many studies demonstrated a reduction in cardiovascular disease events, including mortality [3]. At present, high-dose atorvastatin (titrated to 80 mg daily) or rosuvastatin (40 mg daily) should be the initial regimen since these drugs are more effective at lowering LDL-C than other statins as monotherapy [14-16]. (See "Statins: Actions, side effects, and administration".)

We recognize that some younger patients and vegans may achieve desirable LDL-C on moderate-intensity statins.

The benefit of this approach was evaluated in a trial in which 325 patients with FH were randomly assigned to high-dose atorvastatin (80 mg/day) or conventional dose simvastatin (40 mg/day) for two years [14]. High-dose atorvastatin produced a larger reduction in LDL-C (308 to 149 mg/dL [8 versus 3.9 mmol/L]) than conventional dose simvastatin (321 to 185 mg/dL [8.3 to 4.8 mmol/L]). High-dose atorvastatin also produced a significant reduction in carotid intima media thickness, measured with B-mode ultrasound, compared with an increase with simvastatin.

For patients who have not significantly (by at least 30 percent) lowered their LDL-C on rosuvastatin or atorvastatin, we switch to the other statin. If neither successfully lowers LDL-C, a less potent statin will very occasionally prove more effective. In addition, clinicians should consider patient's noncompliance as a possible explanation of a less-than-expected response to a potent statin.

Second-line therapy — We may use as an additional agent in patients who do not meet cholesterol treatment goals with dietary modification plus maximally tolerated lipid-lowering therapies (eg, statins, ezetimibe) or as an alternative agent in patients intolerant of such therapies. Most adult heterozygotes will not be able to achieve LDL-C goal with maximally tolerated, high-dose statin monotherapy (see 'Goal of therapy' above), which will likely lower LDL-C no more than 55 to 60 percent [12,17,18]. If after three months of compliant statin therapy the LDL-C target has not been reached, we add a second drug to lower LDL-C. However, experts differ on the optimal approach after statin. Most experts recommend ezetimibe, a PCSK9 inhibitor, or both. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Clinical effect' and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Summary and recommendations'.)

In our practice, when a second agent is required, we typically initiate ezetimibe 10 mg daily as the next cholesterol lowering agent based on the results from IMPROVE-IT, and follow this with a PCSK9 inhibitor based on the results from FOURIER when the goal has not been met. Ezetimibe can lower LDL-C by an additional 20 to 30 percent [19]. However, if on statin the patient remains significantly above goal such that a 20 to 30 percent additional reduction will not bring the patient to goal, we consider adding a PCSK9 inhibitor as the next LDL-C lowering therapy. We acknowledge that many insurers will not approve a PCSK9 inhibitor without prior trial of ezetimibe.

While additional lipid lowering therapy produces a further reduction in LDL-C [19-23], there have been no trials in heterozygous FH patients demonstrating improved clinical outcomes in patients already on high-dose statin therapy. However, the FOURIER trial of patients without FH found that a PCSK9 inhibitor (evolocumab) lowered the risk of non-fatal myocardial infarction (MI) and non-fatal stroke. There was no decrease in the risk of cardiovascular death. As patients with FH are at a higher risk of cardiovascular disease events at any LDL-C level compared with those who do not have FH, we believe that FOURIER supports the use of PCSK9 inhibitors to achieve LDL-C goals in these individuals.

While PCSK9 inhibitors are highly effective at lowering LDL-C and have been shown in patients without FH to lower the risk of MI and stroke, many patients may not have access to these drugs due to cost. Even in geographies where they have been approved for use [24,25], they may not be covered by insurance carriers or insurance carriers may require large monthly copayments from patients. Some cost-effectiveness studies have concluded that this class of drug is cost effective despite the absence of direct evidence of cardiovascular disease risk reduction in FH patients [26]. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

PCSK9 combination therapy in patients with heterozygous FH was shown to lead to the nonclinical (ie, surrogate) outcomes of lower LDL-C levels and possible reduction of atherosclerotic plaque in the following studies:

●Maximally tolerated therapy plus alirocumab – In the ODYSSEY I and ODYSSEY II trials, 735 heterozygous FH patients on maximally tolerated lipid-lowering therapy (including statin) were randomly assigned to alirocumab or placebo every two weeks [27]. The primary end point of the percentage change in calculated LDL-C from baseline to 24 weeks was greater with alirocumab (-57.9 percent and -51.4 percent in the two studies, respectively). In both studies, the final LDL-C was about 70 mg/dL (1.8 mmol/L). The results were maintained through 78 weeks. Serious adverse reactions requiring discontinuation occurred in about 3.5 percent of patients, and this rate was similar to that in the placebo group.

In the later ARCHITECT open-label, single-arm study, 104 patients with FH and no ASCVD who were on high-intensity statin were given additional therapy with alirocumab [28]. This treatment resulted in regression of coronary plaque number and composition on coronary computed tomographic angiography over 78 weeks. These imaging findings might reflect regression of lesions and a reduced propensity for plaque rupture (or plaque disruption).

●Apheresis plus alirocumab – In the ODYSSEY ESCAPE trial, 62 patients on lipid-lowering therapy who were undergoing regular lipoprotein apheresis were randomly assigned (2:1, respectively) to receive alirocumab 150 mg or placebo for 18 weeks [29]. The primary efficacy end point, the rate of apheresis treatments over 12 weeks (weeks 7 to 18) standardized to the number of planned treatments, was 75 percent lower with active treatment (p<0.001). The mean preapheresis LDL-C was reduced by 56 percent compared with 5 percent, respectively. Approximately 63 percent of patients in the alirocumab group discontinued apheresis.

Third-line treatment — In patients who remain above LDL-C goal after initial and second-line therapy, historical options for additional intervention have included ileal bypass surgery, portacaval anastomosis, and liver transplantation. These interventions are rarely used in a heterozygous FH patient. Lipoprotein apheresis, which can lower LDL-C by 60 to 70 percent, would also be uncommonly used in a heterozygote.

Bempedoic acid may have a role [30]. It is not available in all locations. When available, it might be reasonable to add it to statin and ezetimibe prior to starting a PCSK9 inhibitor. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bempedoic acid'.)

These therapies, as well as investigational and novel medical therapies, including microsomal triglyceride transfer protein inhibition (lomitapide) and mRNA inhibition of apolipoprotein B are discussed separately. (See "Treatment of drug-resistant hypercholesterolemia".)

Fertile women — Fertile women with FH present special challenges to physicians caring for them, including the potential for pregnancy while on statin therapy, the risks of pregnancy in the presence of advanced coronary artery disease or aortic stenosis, and the use of lipid-lowering therapy during breast-feeding.

We agree with the following recommendations made in the 2008 United Kingdom National Institute for Health and Clinical Excellence Clinical Guidelines and Evidence Review for Familial Hypercholesterolemia [31,32]:

●FH women who are on statin therapy and anticipate becoming pregnant should stop statins three months prior to attempting to conceive. The potential risks to the fetus of statin therapy are discussed separately. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)

●Contraceptive options should be explored with fertile FH patients. For those women who choose to use an oral contraceptive, the potential for an increased risk of a cardiovascular event related to thrombosis and/or elevated lipids needs to be discussed. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

●An assessment of coronary artery disease and aortic stenosis risk should be made prior to conception, particularly in homozygotes. (See "Screening for coronary heart disease" and "Pregnancy and valve disease".)

●Cholesterol measurements should not be performed during pregnancy, as no therapy is safe during pregnancy, perhaps with the exception of LDL-C apheresis.

●There are no contraindications to breastfeeding in these women, but no lipid-lowering therapies should be used, with the possible exception of resin agents.

These issues should be discussed in depth with the patient well in advance of conception and should be repeated periodically.

The issue of whether pregnancy outcomes (mother and child) are worse in women with heterozygous FH was addressed in a Norwegian registry-based study of 2319 births of 1093 such women [33]. Outcomes were compared with those of women (and their children) in the general Norwegian population for the same time period (1967 to 2006).

The following findings were noted:

●The mean prepregnancy total cholesterol was 370 mg/dL (9.59 mmol/L).

●The frequencies of prematurity, low birth weight, and congenital malformations were not significantly different between women with FH and women in the general population (6.8, 5.0, and 3.3 versus 6.2, 5.2, and 3.2 percent, respectively).

RECOMMENDATIONS OF OTHERS — The following guidelines indirectly or directly address the management of low density lipoprotein cholesterol (LDL-C) in adults with familial hypercholesterolemia (FH):

●The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that a non-statin drug may be added to statin therapy in patients with initial LDL-C >190 mg/dL who do not achieve the LDL-C target [34]. The subsequent 2016 American College of Cardiology Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-C lowering allows for the use of nonstatin therapy in statin treated young adults who have not lowered their LDL-C goal below 70 mg/dL or by more than 50 percent if their initial value was ≥190 mg/dL [35].

●The 2019 guidelines for the management of dyslipidemia from the European Society of Cardiology/European Atherosclerosis Society make the following recommendations:

•For individuals without atherosclerotic cardiovascular disease (ASCVD) at very high risk, an LDL-C reduction of ≥50 percent from baseline and an LDL-C goal of <55 mg/dL (1.4 mmol/L), or whichever is lower, should be considered. This recommendation is much stronger for individuals with established ASCVD.

•To reach these goals, it is reasonable to add a PCSK9 inhibitor to statin plus ezetimibe.

●The 2016 National Institute for Health and Care Excellence document recommends the use of evolocumab for the following heterozygous FH patients [36]:

•Those without CVD if the LDL-C is persistently above 5.0 mmol/L (193 mg/dL)

•Those with CVD if the LDL-C is persistently above 3.5 mmol/L (135 mg/dL)

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 5^th to 6^th 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 10^th to 12^th 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

●Homozygotes – Adult patients with homozygous familial hypercholesterolemia (FH), who often have untreated low density lipoprotein cholesterol (LDL-C) values >500 mg/dL (>13 mmol/L), are at very high risk of developing potentially lethal atherosclerotic cardiovascular disease at a very young age. Our approach is intensive LDL-C lowering. (See 'Homozygous individuals' above.)

In addition to a high-dose statin (atorvastatin 80 mg daily or rosuvastatin 40 mg daily), most homozygous patients will require a combination of additional therapies such as ezetimibe, a PCSK9 inhibitor, and potentially LDL-C apheresis. The care of such patients should involve a lipid specialist if one is available. (See 'Referral to a lipid specialist' above.)

●Heterozygotes

•Goal of therapy – For patients with heterozygous FH, the primary goal of treatment is also intensive LDL-C lowering. (See 'Rationale for intense LDL-C lowering' above.)

There is no uniformity of opinion as to the LDL-C goal in heterozygotes. We target an LDL-C of <70 mg/dL. 

We try to achieve very aggressive (lower) LDL-C targets (<55 mg/dL) in patients at the highest risk of cardiovascular disease events. (See 'Goal of therapy' above.)

•Approach

-For adult patients with heterozygous FH, we recommend high-dose statin therapy (atorvastatin 80 mg daily or rosuvastatin 40 mg daily) rather than less intensive therapy (Grade 1A). (See 'Initial drug therapy' above.)

Patients may be started at a lower dose if there is a concern about compliance with a higher initial dose.

-For patients with heterozygous FH who do not achieve their LDL-C goal on high-dose statin, we suggest adding ezetimibe 10 mg daily (Grade 2C).

-For patients who do not approach their LDL-C goal after three months on statin and ezetimibe, we refer the patient to a lipid specialist who should consider the addition of a PCSK9 inhibitor. (See 'Second-line therapy' above and 'Third-line treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Sarah D de Ferranti, MD, MPH, who contributed to earlier versions of this topic review.