Familial Hypercholesterolemia: Advances in Recognition and Therapy

Abstract

Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH.

Familial hypercholesterolemia is a genetic disorder characterized by lifetime elevated plasma low-density lipoprotein (LDL)-cholesterol (LDL-C) levels leading to accelerated atherosclerosis and premature coronary heart disease (CHD).¹ It has an autosomal co-dominant pattern of inheritance.² FH is caused predominately by LDL receptor (LDLR) gene variants of which over 1288 have been identified, of which 79% of these are likely to cause disease.³ FH homozygotes, individuals with two mutated LDLR alleles, are more severely affected than heterozygotes and are classified as either receptor negative (<2% residual activity) or receptor-defective (2%–25% residual activity). LDLR-negative patients have higher LDL-C levels and a worse clinical prognosis.⁴

The LDL receptor binds apolipoprotein B, the main apolipoprotein on LDL particles. The receptor-ligand complex is internalized by endocytosis via clathrin-coated pits and transported to the late endosomal compartment. The acidic environment causes the complex to dissociate, and the LDL particle is degraded in the lysosomal compartment. The receptor is recycled to the cell surface.⁵ When the cholesterol concentration in the hepatocyte falls below a certain level, transcription factors upregulate 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, causing increased cholesterol synthesis, and increased LDLR production, which increases uptake into the hepatocyte. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that limits this process. PCKS9 binds to the LDLR, which is then targeted for lysosomal degradation, decreasing the uptake of cholesterol from the circulation.⁶

Mutations in apolipoprotein apoB, LDL receptor adaptor protein (LDLRAP) and PCSK9 are also known to result in FH. Defects in the apo B gene, most commonly a mutation of Arg3500Gln, affect LDL binding to the LDLR and occur in approximately 5% of FH cases.^5,7 Loss-of-function (LOF) mutations in LDLRAP1 cause an autosomal recessive form of FH; LDLRAP1 protein is necessary for clathrin-mediated internalization of the LDLR by liver cells.⁵ Both gain-of-function (GOF) and LOF mutations of PCSK9 have been described; GOF mutations cause increased LDL-C blood levels due to greater binding of PCSK9 to the LDLR, while LOF mutations result in lower levels.⁶ GOF mutations occur in about 1% of FH cases.⁷

Patients can be homozygous for the same mutation in both alleles of the same gene or can be compound heterozygotes with different mutations in each allele of the same gene. Rarely, patients are double heterozygotes with mutations in two different genes affecting LDLRfunction. The severity of the phenotype depends on residual LDL receptor activity. Phenotypic variability may also occur due to small effect genetic variants or epigenetic influences.⁴ Individuals may also have favorable genes or beneficial lifestyle habits that reduce the impact of a mutation.⁷

Prevalence

FH is more common than the historical estimate of 1 in 500 people.⁷ Recent studies suggest that 1 in 200 is more likely in many populations.^8,9 This suggests that there are up to 34 million people worldwide with FH.⁷ There is increased frequency in particular populations due to founder effects as seen in French Canadians, South African Afrikaners, Jews, Indians, Tunisians, Christian Lebanese, Icelanders, and Finns.¹ Less than 1% of affected patients are diagnosed in most countries. A notable exception is the Netherlands, where a national program to trace all FH patients was instituted in the 1990s.¹⁰ Other countries with increased detection include Norway, Iceland, Switzerland, United Kingdom, and Spain.⁷

Clinical presentation

Untreated men with heterozygous FH (HeFH) typically develop cardiovascular disease (CVD) before age 55 and women before age 60. A significant difference in mean carotid intima-media thickness between children with HeFH and their unaffected siblings was found before the age of 8 years.¹¹ Patients with homozygous FH (HoFH) typically develop CVD at a young age and, if untreated, many die before age 20.⁷ Due to the large accumulation of cholesterol at the valvular level, young children often have symptoms associated with aortic stenosis and regurgitation.⁴ Aortic root disease is a common manifestation of HoFH, and patients often have some degree of atheromatous involvement of the ascending aorta by puberty.¹²

Clinical manifestations of HoFH typically occur during childhood and children may be diagnosed during evaluations for the appearance of xanthomas. These may include both planar xanthomas and tendon xanthomas.^4,13 Tendon xanthomas at any age should make a clinician suspect FH. They most commonly appear in the Achilles tendon and finger extensor tendons but can also be present in patellar and triceps tendons.¹⁴ Tuberous xanthomas or xanthelasma are suggestive of FH only when found in those younger than 20 to 25 years.¹⁴ Cholesterol deposits in tendons and joints can cause tendinitis and joint pain.⁴ Xanthomas can be found by palpation, and increased detection can be done by sonographic evaluation.^7,14 Partial or complete corneal arcus is not specific for FH unless both upper and lower arcs are present in a patient 45 years of age or younger. However, the absence of physical findings does not rule out FH.¹⁴

Diagnosis

There are several sets of criteria for diagnosing HeFH. The Dutch Lipid Clinic Network Criteria (Table 1) uses a scoring system based on family history, clinical history, physical examination, LDL-C, and DNA analysis. A score> 5 makes the diagnosis probable and a score>8 is considered definite FH. It is not used in children.¹⁵ The Simon Broome criteria can be used in children and adults and include cholesterol levels, physical findings, DNA evidence and family history but do not include arcus cornealis.¹⁶ The MEDPED System requires knowledge of LDL-C levels of other family members.¹⁷ At least two fasting measures of LDL-C should be obtained to diagnose FH, and secondary causes (e.g., hypothyroidism, nephrotic syndrome) should be excluded.¹⁸ About 10%–40% of those with a clinical diagnosis do not have an identified mutation found on genetic testing.⁷ Absence of an identified mutation does not exclude the diagnosis of FH.

Table 1–

Dutch lipid clinic network criteria.

			Points
Family history
First degree relative with known premature coronary and vascular disease (men <55 y, women <60 y)			1
First degree relative with known LDL-C > 95th percentile and/or
First degree relative with tendon xanthomata and/or arcus cornealis			2
Children <18 y with LDL-C > 95th percentile
Clinical history
Patient has premature CAD (men <55 y, women <60 y)			2
Patient has premature cerebral or peripheral vascular disease (men <55 y, women <60 y)			1
Physical examination
Tendon xanthomata			6
Arcus cornealis <45 y			4
Laboratory analysis
	mmol/l	mg/dl
LDL-C	>8.5	>330	8
LDL-C	6.5–8.4	250–329	5
LDL-C	5.0–6.4	190–249	3
LDL-C	4.0–4.9	155–189	1
DNA-analysis
Functional mutation in LDLR, APOB, LDLRAP1, or PCSK9			8
Diagnosis of FH is:
Certain when			>8 points
Probable when			6–8 points
Possible when			3–5 points

From: World Health Organization.¹⁵

The American Heart Association recently released an agenda for FH proposing that a diagnosis of FH can be made in the absence of genetic testing. It classifies heterozygous FH by the presence of a family history significant for premature CHD or elevated cholesterol and LDL-C ≥190 mg/dL in an adult or ≥160 mg/dL in a child, confirmed on two occasions; LDL-C > 400 is considered diagnostic of Ho FH.¹⁹ However, there are other proposed criteria for the diagnosis of HoFH, which have been more widely used (Table 2).⁴

Table 2–

Criteria for diagnosis of homozygous FH.

Diagnosis of Homozygous FH

Genetic analysis showing mutations in two alleles at gene locus for LDLR, APOB, PCKS9, LDLRAP1

OR

Presence of untreated LDL >500 mg/dL or treated LDL> 300mg/dL plus: Presence of cutaneous or tendon xanthomas before the age of 10 years

or

Both parents with evidence of heterozygous FH (except for the rare LDLRAP1 mutations)

Note that the range of untreated LDL-C levels in homozygous FH can be lower, especially in children.

From: Cuchel et al.⁴

Other approaches for case finding and diagnosis include those from the National Lipid Association (NLA). FH may be suspected in those under the age of 20 if untreated fasting LDL-C is ≥160 mg/dL or non-high-density lipoprotein (HDL) cholesterol ≥190 mg/dL.¹⁴ The European Atherosclerosis Society suggests that diagnosis of FH can be made by either phenotypic criteria or positive genetic testing. The diagnosis is highly probable in children if the LDL-C is ≥5 mmol/L (190 mg/dL) after 3 months of dietary intervention, ≥4 mmol/L (160 mg/dL) plus a family history of premature CVD and/or high cholesterol in one parent, or ≥3.5 mmol/L (130 mg/dL) and a parent has a genetic diagnosis of FH.²⁰ The yield of genetic testing depends on the criteria used for making the diagnosis of FH.⁸

Risk assessment

In those diagnosed with FH, the risk of CVD can vary widely. All patients should be evaluated for atherosclerosis and other risk factors including smoking, obesity, low HDL, hypertension and diabetes mellitus.¹⁸ Lipoprotein a [Lp(a)] can also be elevated in patients with HeFH and HoFH.^21,22 FH patients with high Lp(a) levels (50 mg/dL and above) are at increased risk of premature vascular disease²³ and require more aggressive LDL-C lowering.⁷

For patients with HoFH, the European Atherosclerosis Society (EAS) recommends that, at diagnosis, patients should receive a comprehensive cardiovascular evaluation. This includes echocardiographic evaluation of the heart and aorta annually and CT coronary angiography every five years if available. In cases of limited access to CT coronary angiography or cardiac MRI, stress testing could be used.⁴

There can be substantial variation in LDL-C levels in patients with both HeFHand HoFH. Typically, the LDL-C drives risk, and patients with higher LDL-C levels are at increased risk.^4,7 For any given LDL-C, the risk of CHD is higher among those with an FH mutation, probably due to lifetime exposure to elevated LDL-C levels.²⁴

Risk assessment algorithms and tables should not be used in patients with FH since they are at high lifetime risk. Almost all FH patients require medication.^14,18

Identifying index cases

Suggested approaches to identify those with FH include universal, opportunistic or cascade screening. Cascade screening is thought to be the most cost-effective approach for identifying new FH subjects. It is important to be able to recognize index cases, and other causes of hypercholesterolemia should be excluded. Ideally, a scoring system such as the Dutch Lipid Clinic Network criteria can be used in adults to establish the diagnosis and, if >5, molecular genetic testing would be done. If a mutation is found, all first-degree relatives should be offered genetic testing.⁷ However, this approach is difficult to implement in countries that do not have a centralized health system. In addition, genetic testing is still expensive in the United States and frequently not covered by insurance.

Screening recommendations

Identifying and controlling dyslipidemia in youth may lead to reduction of CVD risk later in life. There is evidence that 30%–60% of children with dyslipidemias are missed if family history of premature CVD or cholesterol disorders is used as the primary factor in determining lipid screening for children. Childhood is also the best time to discriminate between FH and non-FH using elevated LDL-C levels.²⁰ The National Heart, Lung, and Blood Institute Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents recommended universal screening in children ages 9–11 and again between the ages of 17 and 21. Screening between the ages of 2 and 8 is recommended if there is a family history of hyperlipidemia and/or premature CVD. They should also be screened if the patient has diabetes, hypertension, or body mass index ≥95th percentile.²⁵

The NLA recommends universal screening at ages 9 to 11 years with a fasting lipid profile or non-fasting non-HDL-C measurement. A non-fasting non-HDL-C ≥ 145 mg/dL necessitates further evaluation with a fasting lipid profile. In the presence of a positive family history of hyperlipidemia or premature CVD, screening should occur earlier, but not before age 2 because of increased variability of levels prior to this age. All individuals should be screened by age 20.¹⁴

The EAS Consensus Panel recommends that children with suspected HeFH be screened as young as five years. If HoFH is suspected, children should be screened as early as possible. Depending on practical and cost considerations, universal screening of children may be another option.²⁰

A consensus panel in Belgium recommended that screening for HeFH should only be performed in children >2 years when HeFH has been identified or is suspected in one parent.²⁶ In Australia, a consensus model of care was developed. Children ≥5 years should be tested for FH after the diagnosis of FH has been made in a parent and should only be genetically tested after a mutation has been identified in a parent or first-degree relative.²⁷

Challenges of screening

There is controversy regarding the appropriateness of universal screening. One reason is that there is weak evidence to support this approach because implementation results have not been reported by any country.²⁸ Cost and resource issues, the potential for false positives, and a possible adverse psychological impact of screening are also concerns that have been raised. It is unclear if genetic discrimination by insurance companies would occur.^13,28

On the other hand, there is no consensus regarding the optimal cascade screening program; any approach can be difficult to implement. Even the most basic requires significant time and trained personnel to identify index cases, track families and test, as well as analyze the results. Often, additional people must be hired or a funded centralized service set up by the country. An FH database needs to be created and an accredited molecular genetics laboratory involved. Cascade screening may not be feasible for general practitioners as family members are often outside their area of care. Also, direct contact by medical staff with family members has been shown to be superior to the recruiting of family members by the index case.²⁸ As a result, an extensive infrastructure is necessary to implement a cascade-screening program and for this reason, there are only a few such programs in the world.

National registries may be useful in overcoming the challenges of screening and case finding. The FH Foundation is working on a registry of patients with FH in the United States in order to improve case finding and treatment.²⁹

Lifestyle management

All patients diagnosed with FH should be educated about lifestyle management. Smokers should be strongly encouraged to stop smoking and, when necessary, should be referred to a specialized tobacco program. A dietitian should discuss a healthy diet with the entire family.⁷ This includes encouraging intake of whole grains, low fat dairy products, beans, fish, lean meats as well as fruits and vegetables. Patients should limit alcohol consumption. Plant sterols and stanols may be considered as an adjunctive therapy as they have been shown to lower LDL-C.^7,18,30 Patients with HeFH can have a significant response to reduction of saturated fat, although this may be less effective in HoFH.⁴ Regular physical activity should also be incorporated into the lives of FH patients.⁷ However, some may need stress testing prior to initiating an exercise program.¹⁸ In high-risk FH patients, low dose aspirin should be used and should be considered in those at lower risk.¹⁸

In children, lifestyle management is important to prevent the development of additional risk factors, primarily obesity.¹³ The EAS consensus panel recommends that <30% of calories come from total fat, <7% of calories from saturated fat, and <200 mg of cholesterol a day. A heart healthy diet, including a Mediterranean diet, has sufficient energy for normal growth. Annual or biannual monitoring of weight, growth and developmental milestones should be conducted.²⁰ The NHLBI recommends that plant sterol and stanol esters can be used after the age of 2 years, and short-term studies have shown no harmful effects. The water-soluble fiber psyllium can be added at a dose of 6 g/d for children 2–12 years, and 12 g/d for those ≥12 years.²⁵ Lifestyle modifications are important in long-term management, and may reduce LDL-C by 10%–15%.³¹

Treatment goals

It is recommended that lipid-lowering therapy be started as early as possible. In patients with HeFH, a 50% reduction in plasma LDL-C is the initial aim.¹⁸ Table 3 shows additional LDL-C treatment goals in adults and children.^7,14,18,25

Table 3–

Proposed treatment goals.

Adults

Initial aim: 50% reduction in LDL-C

LDL-C of <2.5 mmol/L (<100 mg/dL)

LDL-C of <1.8 mmol/L (<70 mg/dL) if hx of coronary heart disease or diabetes

Children

50% reduction in LDL-C

OR

LDL-C of <130 mg/dL

Statins

Statins work by decreasing cholesterol synthesis and thereby upregulating LDLR. They are the mainstay of treatment for the management of FH and should be initiated immediately on diagnosis.^7,18 In a meta-analysis reviewing 174,000 participants in 27 randomized trials, statins reduced the risk of major CVD events by 21% for each 1.0 mmol/L (about 40 mg/dL) reduction in LDL-C.³² Low potency statins are generally inadequate in FH, and initial treatment is the use of moderate to high doses of high potency statins.^7,14 Medications to consider include atorvastatin 80 mg, rosuvastatin 40 mg, or pitavastatin 4 mg daily. In patients with decreased renal function, atorvastatin may be preferable because it is not excreted by the kidney.²⁰ Even in patients with HoFH, statins have been shown to reduce CVD- and all-cause mortality³³; the response to statins may be due to decreased hepatic secretion of apoB or to upregulation of residual activity of LDLR.¹⁸ However, some patients who are homozygous for LDL receptor mutations with no receptor activity can respond to lipid lowering therapy.¹⁰

Four to six weeks after initiating treatment, clinical assessment of efficacy and safety should be done.⁷ Potential drug–drug interactions can be seen between drugs metabolized by cytochrome (CYP) P450 and statins such as lovastatin, simvastatin and atorvastatin. Rosuvastatin and fluvastatin interact with drugs metabolized by CYP 2C9.²⁰ Most common adverse affects are muscle symptoms, which are dose-dependent and vary among statins.¹⁸ If the initial statin is not tolerated, an alternative statin or every-other-day statin therapy should be considered. For those who cannot tolerate any statin, combination drug therapy will likely be required. Ezetimibe, bile acid sequestrants, and niacin can be considered. These medications are also possible additions if adequate LDL-C reduction is not attained with a maximum tolerable dose of statin.¹⁴

The age at which statins should be started has been debated. Pravastatin is approved in the United States for children with HeFH starting at age 8, and lovastatin, simvastatin, fluvastatin, atorvastatin, and rosuvastatin starting at age 10. Children with HoFH should be treated as soon as they are diagnosed.¹⁴ The NHLBI has a general recommendation not to initiate statins until the age of 10; but if a patient has multiple risk factors, starting at a younger age can be considered.²⁵ The EAS recommends that treatment should be initiated at the lowest recommended dose and up-titrated. Although a weak statin, pravastatin is considered a safe initial drug in children.²⁰ In a 2014 Cochrane review investigating the effectiveness and safety of statins in children with FH, eight randomized controlled studies were reviewed. Statins reduced the mean LDL-C concentration at all time points. The risks of myopathy and adverse events were very low in both the statin and control groups.³⁴ Longer-term studies are necessary to address safety concerns as well as determine if there are any possible effects on growth and sexual maturation.

Ezetimibe

Ezetimibe selectively inhibits the intestinal cholesterol uptake transporter Niemann-Pick C1 Like 1 protein.³⁵ This decreases cholesterol return to the liver and leads to upregulation of LDLR. Ezetimibe prevents the uptake and absorption of cholesterol in the small intestine without reducing absorption of triglycerides, fat-soluble vitamins, or bile acids.³⁶ Studies have shown that, due to additive effects, co-administration of ezetimibe with a statin leads to a significant improvement in LDL-C.^25,35–37 It has been estimated that doubling the dose of statin therapy can lead to a 6% reduction in LDL-C, but the addition of ezetimibe to a statin could lead to reductions of 15%^–20% or more.³⁵ Response to the addition of ezetimibe to a statin in patients with FH can vary from 4.7 to 39.2 percent further decrease in LDL C.³⁸

There has been controversy about whether the addition of ezetimibe to a statin improves CVD outcomes. Although not directly applicable to FH, the IMPROVE-IT trial showed a significant decrease in major atherosclerotic CVD events in post-acute coronary syndrome patients treated with ezetimibe plus simvastatin compared with simvastatin alone. IMPROVE-IT also showed no difference between the groups in rates of adverse events including liver enzyme elevation, muscle problems or cancer incidence.³⁹

In the United States and Europe, ezetimibe is approved from the age of 10 years.²⁰ In a study of patients aged 10–17 with HeFH, coadministration of ezetimibe with simvastatin resulted in higher LDL-C reduction than simvastatin alone. It was also safe and well tolerated for up to 53 weeks.⁴⁰ In another trial looking at the efficacy and safety of ezetimibe monotherapy in children with HeFH (91%) or nonFH, 138 children aged 6 to 10 years were enrolled in a 12-week, randomized, double-blind, placebo-controlled study. LDL-C was reduced by 27%, and ezetimibe was well tolerated.⁴¹

Most FH guidelines recommend ezetimibe as the next medication to add to a statin for combination therapy of FH.^4,18

Bile acid sequestrants

Bile acid sequestrants prevent the eneterohepatic reuptake of bile salts by binding them within the intestinal lumen. This results in a depletion of bile salts in the liver and a signal for further production. The amount of intracellular cholesterol decreases as bile salts are synthesized which triggers an increased production of LDLR. This, in turn, causes increased clearance of circulating LDL-C.²⁵

Bile acid sequestrants decrease LDL-C by 10% to 20% depending on dosage. Side effects include constipation, bloating, nausea and abdominal pain. The older medications, cholestyramine and colestipol, have more side effects than do colesevelam. Colesevelam has fewer drug interactions than do colestipol and cholestyramine. The addition of a bile acid sequestrant to a statin plus ezetimibe produces further LDL-C lowering.⁴²

Colesevelam has been studied in pediatric populations and is approved for use in boys and postmenarchal girls aged 10 to 17 years as monotherapy or in combination with a statin. It is available in tablet or a powder formulation.³¹ In a study of 194 children aged 10 to 17 years with HeFH who were randomized to receive colesevelam 1.875 g/d, 3.75 g/d or placebo for 8 weeks, there was a significant decrease in LDL-C with the use of colesevelam compared to placebo. Diarrhea, nausea, vomiting and abdominal pain were the most common adverse events.⁴³

Colesevelam dosage does not need to be adjusted in hepatic or mild-moderate renal impairment. However, it can bind to other drugs in the gastrointestinal tract, leading to decreased absorption. Therefore, drugs with known interactions should be given at least four hours prior to colesevelam.⁴⁴ Cholestyramine and colestipol interfere with the absorption of many medications and must also be separated from other medications by at least four hours.

Niacin

Niacin has been used for decades for LDL-C lowering.¹⁴ It results in decreases of LDL-C of approximately 14% and lowers Lp(a) by up to 25%. Triglyceride values can fall by up to 50%.³⁶ Due to adverse effects of flushing, hepatic dysfunction, myopathy, glucose intolerance, and hyperuricemia, it is not generally used in pediatric patients.³¹

In the Coronary Drug Project, monotherapy with niacin decreased non-fatal myocardial infarction initially and mortality 9 years later.⁴⁵ However, in recent studies adding niacin to patients already treated with statin or statin plus ezetemibe and achieving LDL-C levels of about 60 mg/dL, the addition of niacin did not show a CVD outcomes benefit.^46,47 Due to its significant side effects, and the availability of more effective medications, niacin is used infrequently, and recent guidelines do not recommend its use.⁴⁸

Pregnancy

Before starting a statin, women of childbearing age should receive pre-pregnancy counseling. Three months prior to conception, statins and other systemically absorbed agents should be discontinued.¹⁸ During pregnancy and lactation, statins, ezetimibe, and niacin should not be used and must be discontinued immediately in the event of an unplanned pregnancy. Treatment with colesevelam is safe but can cause gastrointestinal side effects. If there is significant atherosclerotic disease or if the patient has HoFH, apheresis is another option.¹⁴

Lipoprotein apheresis

Lipoprotein apheresis is an extracorporeal method of removing apo-B containing lipoproteins from the circulation and is FOOD and Drug Administration (FDA) approved for patients who are not at LDL-C treatment goal or have ongoing symptomatic disease on maximally tolerated lipid-lowering therapy.^14,18 Apheresis has been found to improve CVD outcomes, atherosclerosis and aortic fibrosis, as well as endothelial function.¹⁸ Many HoFH patients will require LDL apheresis despite high dose statins and combination drug therapy. Recently approved medications have had an impact on the need for apheresis.

There are several apheresis methods and all lower LDL-C and Lp(a) by 50 to 70% after a single treatment. Regression of cutaneous xanthomas can occur with long-term treatment.⁴ In the United States, extracorporeal precipitation is done with dextran sulfate or heparin. Contraindications to heparin include heparin sensitivity and hemorrhagic diatheses. Angiotensin-converting enzyme inhibitors are generally contraindicated with dextran sulfate because of bradykinin reactions and risk of severe hypotension.^4,18 Side effects of apheresis include allergic reactions, hypotension, abdominal pain, nausea, hypocalcemia and iron deficiency anemia, but these are uncommon.⁴ Venous access can be challenging in very young patients but a peripheral venous cannula can be used. In patients with HoFH, treatment should be started ideally by age 5 and not later than 8 years.⁴

The costs are significant and are comparable with hemodialysis.¹⁸ However, it is considered cost-effective in HoFH.⁴ Patients generally require treatment weekly or every two weeks. To reduce the rebound in LDL-C, statins and other medications should be continued.¹⁸

Mipomersen

In January 2013, the FDA approved mipomersen for the treatment of adults with HoFH. It is a single-stranded antisense oligonucleotide that targets the messenger RNA that codes for apoB-100. Translation of mRNA is blocked, decreasing synthesis of apoB. This causes less VLDL to be released by the liver and thus decreases LDL-C levels.³⁶ It is dosed at 200 mg once weekly as a subcutaneous injection.

Various trials have shown that mipomersen decreases LDL-C, apoB, and Lp(a) by 25%–37%, 26%–38%, and 21%–31%, respectively. The most common adverse events were injection site reactions and influenza-like symptoms. Increases in alanine aminotransferase three or more times the upper limit of normal were found in 6%–12% of patients as well as increases of hepatic fat content by 5%–16%.^49–52

There appears to be no interaction between statin drugs and mipomersen. Fat accumulation in the liver is the most serious complication and is due to impaired very low density lipoprotein (VLDL) secretion. It is available only through a Risk Evaluation and Mitigation Strategy (REMS) program. Its use has not been approved in the European Union.³⁶

Lomitapide

Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP), a molecule that transfers triglycerides to apoB for the production of VLDL. It results in a reduction of LDL-C and was approved for the treatment of adults with HoFH in December 2012 in the United States and in July 2013 in Europe.⁵³ Like mipomersen, it is only available through a REMS program.

Studies have demonstrated that lomitapide decreases LDL-C by 38%–51%, and the most serious adverse events are increased hepatic fat and elevations of aminotransferase levels.^54–56 At this time, the effect of lomitapide treatment on cardiovascular events in HoFH has yet to be determined.⁵³

The initial recommended dosage is 5 mg once daily. This can be increased to 10 mg after two weeks. At a minimum of 4-week intervals, the dose can be titrated to 20, 40, and a maximum of 60 mg. It should be given fasting, at least two hours after an evening meal. Usual side effects are gastrointestinal reactions including nausea, flatulence, and diarrhea. Lomitapide can decrease the absorption of fat-soluble vitamins and fatty acids, and supplementation with vitamin E, linoleic acid, alpha-linolenic acid, eicosapentaeonic acid, and docosahexaenoic acid is advised.⁵³ Patients should be on a diet in which less than 20% of calories are from fat.⁵³

Lomitapide is metabolized via CYP P450 3 A4; and for this reason, moderate and strong inhibitors of CYP3A4 are contraindicated. A maximum of 30 mg should be given if the patient is on a weak inhibitor (e.g., verapamil, amiodarone, amlodipine). If on atorvastatin, the lomitapide dose should not exceed 30 mg and if on simvastatin, should not be higher than 20 mg. In patients with end stage renal disease or mild hepatic impairment, the maximum dosage is 40 mg daily. Lomitapide can increase warfarin levels.⁵³

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

PCSK9 is a serine protease that is secreted by the liver and regulates the degradation of the LDLR. The higher the level of serum PCSK9, the lower the LDLR and vice versa.³⁶

Inhibition of PCSK9 is an emerging therapy and small interfering RNA drugs and monoclonal antibodies are under development.⁶ The concept behind siRNA is that it can direct sequence-specific degradation of mRNA and thereby suppresses the synthesis of the corresponding proteins. Alnylam Pharmaceuticals has produced ALN-PCS, a PCSK9-specific siRNA that is formulated in a lipid nanoparticle. In a phase 1 placebo-controlled study, subjects receiving ALN-PCS, had a mean 70% reduction in circulating PCSK9 plasma protein and a 40% reduction in LDL-C from baseline relative to placebo. Adverse events were mild to moderate in severity and were present in 79% in the ALN-PCS group and 88% in those taking placebo.⁵⁷ Ongoing phase 1 trials are underway.

Monoclonal antibodies bind to PCSK9 and prevent the formation of the PCSK9/LDLR complex, leading to more available LDR receptors. When a PCSK9 mAb is added to a high intensity statin, up to 100% of the PCKS9 is bound by mAb and there is increased uptake of LDL-C, producing a 50% reduction.⁶ Two mAbs for PCKS9 have been approved and a third is in late phase clinical trials. These agents are given subcutaneously every 2 to 4 weeks by use of pen injectors that minimize inconvenience. Because they do not inhibit CYP P450 and are not metabolized by it, they do not interfere with statin metabolism.³⁶

Alirocumab

In phase 2 trials, alirocumab demonstrated reductions in LDL-C of up to 72.4% in patients receiving concomitant statin or statin plus ezetimibe therapy.⁵⁸

Alirocumab has been studied in patients with HeFH. In ODYSSEY FH I mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL), a 57.9% decrease compared to placebo. In FH II, it decreased from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL), a 51.4% decrease versus placebo. The reductions were maintained through week 78. Injection site reactions were the most common side effects.⁵⁹

In a post-hoc analysis of a long-term safety trial, major atherosclerotic CVD(ASCVD) events were reduced in patients on alirocumab by nearly 50% compared with standard therapy.⁶⁰ A CVD outcomes trial with alirocumab is in progress.

Alirocumab is dosed at either 75 mg or 150 mg every two weeks. The indication in the U.S. labeling is for use as an adjunct to diet and maximally tolerated statin therapy for adults with HeFH or clinical ASCVD who require additional lowering of LDL-C.⁶¹

Evolocumab

Evolocumab has also been shown to reduce LDL-C in patients with FH. A small trial in patients with HoFH showed reduction in LDL-C only in patients who had residual LDLRactivity.⁶² A larger study, TESLA Part B, was a phase 3 randomized trial that recruited patients with HoFH on lipid regulating therapy but not on apheresis. They were randomized to receive evolocumab 420 mg or placebo every four weeks for 12 weeks. Compared to placebo, evolocumab reduced LDL-C at 12 weeks by 30.9%. There were no serious adverse events.⁶³

Patients with HeFH on stable lipid-lowering therapy treated with evolocumab 140 mg every two weeks had a significant reduction in mean LDL-C of 59.2%. Those taking 420 mg monthly had a 61.3% decrease. Evolocumab was well tolerated and adverse events were similar to placebo.⁶⁴

Post hoc analysis of data from two yearlong phase 3 safety trials showed decreased CVD events by over 50% with evolocumab compared with standard of care therapy.⁶⁵ A CVD outcomes trial is in progress.⁶⁶

Evolocumab is dosed at 140 mg subcutaneously every two weeks or 420 mg once per month. The U.S. indications are as an adjunct to diet and maximally tolerated statin therapy for adults with HeFH or clinical ASCVD who require additional lowering of LDL-C and in addition to other LDLC lowering therapies in patients with HoFH who require additional LDL-C lowering. Patients with HoFH should be treated with 420 mg once per month.⁶⁷

Bococizumab

Bococizumab is the third PCSK9 monoclonal antibody in development, which is still in phase 3 clinical trials. One trial, SPIRE-FH, plans to recruit 300 patients with HeFH and have them randomized to receive bococizumab 150 mg every two weeks or placebo for 12 months. The primary outcome is the percent change from baseline in LDL-C at week 12.⁶⁸ SPIRE-1 and SPIRE-2 are five year trials assessing bozocizumab compared to placebo in reducing the occurrence of major cardiovascular events in high risk subjects and they are estimated to be completed in 2018.^69,70

Liver transplantation (LT)

LT has been performed rarely if the FH patient cannot tolerate pharmacotherapy or lipoprotein apheresis.¹⁴ It can result in a significant decrease in LDL-C levels since it provides a liver with functional LDLR, thereby correcting the molecular defect. It can be done alone or in combination with a heart transplant. Disadvantages include surgical morbidity and mortality, a lack of donors, and the need for long-term treatment with immunosuppressant therapy. LT has been done in a number of centers in children who do not have access to, or who are not candidates, for LDL apheresis.⁷¹

Gene therapy

The success of LT in reducing LDL-C provides indirect evidence that targeted gene therapy toward the liver has potential effectiveness. It suggests that hepatic reconstitution of LDLR expression may be sufficient to correct the metabolic disturbance. Gene transfer can be done ex vivo, by isolating autologous cells, performing in vitro genetic modification, and then reimplanting the transduced cells. This approach has not been successful. With an in vivo approach, the vector is delivered directly to the organ.⁷² The goal of gene therapy in FH is to deliver a single vector administration to achieve lifetime correction of LDL-C levels. A phase 1/2 clinical trial using an AAV vector is currently in progress.⁷³

Conclusion

FH is a common genetic disorder that causes elevated LDL-C levels and therefore increases the risk of premature CVD. FH is underdiagnosed and undertreated with fewer than 1% of patients diagnosed in many countries. Approaches to identifying these patients include universal, opportunistic, or cascade screening but there is controversy regarding the best approach. It is important for clinicians to recognize FH, and the diagnosis should be made based on family and clinical history, physical exam, LDL-C levels and, if possible, DNA analysis.

Lipid-lowering therapy should be started early, and high-intensity statins are the mainstay of treatment. Combination therapy is often required to obtain substantial LDL-C reduction. Ezetimibe can be added to a statin. Addition of a bile acid sequestrant can also be beneficial. Many patients with HoFH have required lipoprotein apheresis, but new treatments, including mipomersen and lomitapide can make a significant difference. The approval in 2015 of the PCSK9 inhibitors, alirocumab and evolocumab, has great potential for allowing substantial LDL-C reductions in patients with heterozygous FH and many patients with homozygous FH; CVD outcomes trials with these agents are underway. With current therapy, the marked elevation in risk of CVD events in FH patients can be reduced substantially.

Abbreviations and Acronyms

ASCVD

atherosclerotic cardiovascular disease

CHD

coronary heart disease

CVD

cardiovascular disease

CYP

cytochrome

EAS

European Atherosclerosis Society

FDA

Food and Drug Administration

FH

Familial hypercholesterolemia

GOF

gain of function

HeFH

heterozygous familial hypercholesterolemia

HoFH

homozygous familial hypercholesterolemia

LDL

low-density lipoprotein

LDL-C

low-density lipoprotein cholesterol

LDLR

low-density lipoprotein receptor

LDLRAP

low-density lipoprotein receptor adapter protein

LOF

loss of function

LT

liver transplantation

Lp(a)

lipoprotein a

NLA

National Lipid Association

REMS

Risk Evaluation and Mitigation Strategy

VLDL

very low-density lipoprotein