Modern Management of Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is a common genetic disorder that can manifest clinically as both the severe homozygous (HoFH) form that often presents in childhood and the commoner heterozygous (HeFH) form that is typically identified in adults. The majority of genetic causes are due to defects in low-density lipoprotein (LDL) receptor synthesis and action. Until recently, it was exceedingly difficult to achieve the goal of a 50% reduction in LDL-cholesterol or LDL-C < 70–100 in these patients. Established therapies include statins, niacin, bile-acid sequestrants, and ezetimibe in various combinations. The recent advent of monoclonal antibodies to PCSK9 (evolocumab and alirocumab) has revolutionized the management of FH and results in a substantial reduction in LDL-C and also reductions in Lp(a). In addition, the previous ushering in of antisense therapy against apoB (mipomersen) and inhibition of microsomal transfer protein (lomitapide) for use in HoFH greatly enhanced our ability to manage refractory hypercholesterolemia in these patients. Hence, the therapeutic landscape for this common disorder has changed dramatically for these patients, with a strong promise for a reduction in cardiovascular events.

Introduction

Familial hypercholesterolemia (FH) is an autosomal codominant disorder that is associated with a 10–20-fold increase in risk of cardiovascular events that occur at an early age.¹ Men with heterozygous FH have an ∼50% risk of having a cardiovascular event before the age of 50 years, and women have a similar risk by the age of 60–65 years.² Individuals with homozygous FH have profound hypercholesterolemia with untreated low-density lipoprotein-cholesterol (LDL-C) concentrations of 450–1100 mg/dL, and a mean age of death from cardiovascular disease of about 19 years in the absence of LDL-lowering treatment.³ Fortunately, the current availability of seven classes of LDL-lowering medications with complementary mechanisms of actions, as well as the availability of LDL/lipoprotein apheresis for FH patients with refractory hypercholesterolemia, has greatly improved our ability to achieve sufficient LDL-C lowering to attenuate or possibly prevent the development of cardiovascular disease in patients with FH.

The risk of atherosclerosis in FH is driven primary by the marked elevation of LDL-C concentrations in affected patients, but higher levels of lipoprotein(a) are an additional risk factor that may double the risk in some patients. The results of a recent study suggested that the risk of cardiovascular events is actually higher in patients with genotypically documented FH compared with individuals with matched LDL-C concentrations, but the presumed mechanism of this association is the lifelong exposure to severe hypercholesterolemia in FH patients in comparison to hypercholesterolemia acquired later in life in individuals who do not have FH.⁴

Since severely elevated LDL-C levels are the primary contributor to atherogenesis in FH, the primary goal of treatment is to lower the LDL-C concentration to a level that is sufficient to prevent the development of atherosclerosis and cardiovascular events. On the basis of the results of a variety of clinical trials, the mean level of LDL-C in patients with cardiovascular disease at which progression of atherosclerosis is stopped is about 69 mg/dL.⁵ Since atherosclerosis is a progressive disease that starts early in life, early initiation of LDL-C-lowering treatment is an important strategy for managing patients with FH.⁶ It is anticipated that initiation at a young age of moderately aggressive LDL-C-lowering treatment will have a greater impact on the lifetime risk of cardiovascular events compared with more aggressive LDL-C lowering that is initiated later in life, particularly when treatment is not started until after evidence of atherosclerosis is already present.

Early Treatment is Needed

For children with heterozygous FH, it is recommended to initiate treatment with a statin by the age of 8–12 years, with consideration of adding adjunctive medications as needed.⁶ All of the statins are FDA approved for treatment of children with FH at the age of 10 years, and pravastatin is approved for use at the age of 8 years. For children with homozygous FH, LDL-C-lowering treatment should be initiated as soon as the diagnosis is identified and may necessitate the implementation of treatment with LDL/lipoprotein apheresis to avert the development of childhood onset of cardiovascular events and early death.⁷ Successful implementation of these treatment goals requires identification of children at risk, so an important principle in management of FH is universal cascade screening of children who may be affected by FH.^6,8 Cascade screening refers to the principle of testing all first degree relatives of a patient known to have FH. FH can be identified by the age of 1 year, but it is recommended that screening of children for FH be completed by the age of 8–10 years. If both parents have FH, the risk of homozygous FH is 25% in their offspring, so all of their children should be tested within the first 1–2 years of life.

Genetic Basis for FH

FH is most commonly (75%–85% of cases) caused by a variety of mutations in the LDL-receptor that reduce the number of functional LDL receptors that are available for removal of LDL particles from plasma by the liver.⁹ About 10%–15% of cases of FH are caused by mutations in apolipoprotein B, the primary protein in LDL that is the ligand for the LDL-receptor, resulting in decreased affinity of apo B for the LDL receptor and reduced LDL-receptor-mediated clearance of LDL from plasma. Less than 1%–2% of cases of FH are caused by gain-of-function mutations in PCSK9 that accelerate targeted degradation of the LDL receptor.⁹ Homozygous (or compound heterozygous) mutations in ARH very rarely cause FH, resulting in defective internalization of the LDL receptor-LDL complex.¹⁰ In many studies, up to 1 out of 3 patients with FH do not have an identifiable mutation in any of these proteins, which suggests that either additional mutations in other currently unrecognized genes may cause FH, or there may be polygenic forms of FH that segregate in a pattern that appears to be autosomal dominant.¹¹

The common biochemical abnormality resulting from mutations in the LDL-R, apo B, PCSK9, and ARH is decreased capacity for clearance of LDL particles from plasma by the LDL receptors in the liver. For this reason, the majority of the current medications work by upregulating the LDL receptor. This is an effective strategy among patients with heterozygous FH, because they have one normal LDL-receptor allele that can be upregulated. In addition, patients with homozygous FH (or compound heterozygous or double heterozygous FH) who have mutations that only partially reduce LDL-receptor function can still respond moderately well to medications that upregulate the LDL-receptor.

Unfortunately, among patients with homozygous FH caused by two null mutations in the LDL receptor, pharmacologic strategies that work by upregulating the LDL receptor are minimally effective, since there is minimal or no functional LDL receptor activity that can be upregulated.³ LDL/lipoprotein apheresis is an efficacious option for these patients, as well as two newer medications, mipomersen (antisense to ApoB) and lomitapide (microsomal transfer protein inhibitor) that function by inhibiting production of very low-density lipoprotein (VLDL), the precursor of LDL.¹² These drugs will be addressed after covering the standard LDL-lowering medications.

Lifestyle Modification

In all patients with FH, a dietary reduction in saturated fat of <7% needs to be adhered to as well as at least 150 min of physical activity per week. Also avoiding dietary trans fatty acids (<1%) and encouraging intake of fiber of around 20–30 grams/day, increased intake of fatty fish and plant stanols (2 grams/day) could be beneficial. All of these measures may result in at least a 10%–20% reduction in LDL-cholesterol.² Smoking should be avoided by everyone, but this is especially important for patients with FH.

Standard Medications

The standard four classes of LDL-C-lowering medications are statins, ezetimibe, niacin, and bile-acid sequestrants (Table 1). Fibrates, such as fenofibrate and gemfibrozil, are occasionally used as adjunctive LDL-C-lowering agents, but their efficacy is low (up to 10%–15%) and their use in combination with statins is associated with increased risk of myopathy/rhabdomyolysis and hepatotoxicity, particularly for gemfibrozil. Statins are the most potent of these four classes of medication, lowering the LDL-C concentration up to 60%, with other drugs having a maximal LDL-C-lowering efficacy of 20%–30% (Table 1). It is recommended to use a high-potency statin (atorvastatin and rosuvastatin; simvastatin and pitavastatin have intermediate potency) in patients with FH and to titrate the dose to the highest FDA-approved dose, as tolerated to achieve at least ≥50% reduction in LDL-cholesterol or LDL-C < 70–100 mg/dl.

Table 1.

LDL-Lowering Drugs for Treatment of FH

A. Standard medications

Statins

Lovastatin, 10–80 mg orally daily

Simvastatin, 10–40 mg orally daily (80 mg allowed only if already treated at this dose for >1 year)

Pravastatin, 10–80 mg orally daily

Atorvastatin (high-potency statin), 10–80 mg orally daily

Fluvastatin, 20–80 mg orally daily

Rosuvastatin (high-potency statin), 5–40 mg orally daily

Pitavastatin, 1–4 mg orally daily

Ezetimibe, 10 mg orally daily

Bile acid sequestrants

Cholestyramine, 4–8 grams powder orally BID or TID

Colestipol, 5–10 grams powder orally BID or TID

Colesevelam (better tolerated), 1.875 grams orally BID

Niacin (immediate-release and intermediate-release preparations)–titration up to 3–5 grams daily can be achieved with immediate-release niacin in some patients. Maximum recommended daily dose of intermediate- and slow-release niacin is 2 grams.

B. Adjunctive medications

Anti-PCSK9 antibody drugs

Alirocumab, 75 or 150 mg SQ biweekly

Evolocumab, 140 mg SQ biweekly or 420 mg SQ once monthly

C. Additional options restricted for only homozygous FH

Note: Both drugs require an REMs program, prescriber certification, and frequent laboratory monitoring during treatment.

Mipomersen-antisense oligonucleotide for apolipoprotein B, 200 mg SQ weekly

Lomitapide-inhibitor of MTP, 5–60 mg orally daily

FH, familial hypercholesterolemia; LDL, low-density lipoprotein; MTP, microsomal triglyceride transfer protein.

Among patients with statin intolerance, lower doses of high-potency statins, alternate-day therapy, or possible use of lower potency statins may be necessary, but even a low dose of atorvastatin 5 mg daily may still lower the LDL-C concentration by 26%–28%. This is an insufficient magnitude of LDL-C lowering for a patient with FH, but this amount of LDL-C lowering in combination with adjunctive medications can produce adequate control of hypercholesterolemia in many patients with heterozygous FH.

It is rare for patients to achieve adequate LDL-C lowering in response to monotherapy with a statin.¹³ The addition of ezetimibe 10 mg daily is an attractive second drug to add to the treatment regimen, which may lower the LDL-C by an additional 18%–20%, with a small proportion of patients being hyperresponsive. If the LDL-C concentration remains elevated after treatment with a dual regimen of a statin in combination with ezetimbe, a third medication can be added, possibly niacin or a bile-acid sequestrant, both of which may lower the LDL-C concentration by 14%–18%, but possibly up to 20%–30% at higher doses. Recently, the FDA issued an advisory cautioning about the use of statin therapy in combination with niacin in patents with CVD given the null results in recent clinical trials. However, we believe that niacin can be used in combination with a statin in FH for the purpose of achieving additional LDL-C lowering. These drugs in monotherapy or in combination are less efficacious in patients with homozygous FH.

Specialty Medications for Homozygous FH

Mipomersen and lomitapide are two specialty medications that were FDA approved in January 2013 and December 2012, respectively, for the narrow indication for treatment of patients with homozygous FH. Mipomersen is an antisense oligonucleotide for apo B that binds to apo B mRNA and blocks translation of apo B as well as targeting the apo B mRNA for degradation by RNAse H.¹² Treatment with mipomersen by weekly 200 mg subcutaneous injections lowers the concentrations of LDL-C and apo B by an average of about 30%, as well as significantly lowering the concentration of lipoprotein(a) by 10%–20%. The LDL, apo B, and lipoprotein(a)-lowering efficacy is sustained for at least up to 4.5 years.^14,15 Toxicity from mipomersen can include injection site reactions, hepatotoxicity with transaminase elevations and/or hepatic steatosis, and flu-like reactions. The results of recently published data demonstrated an 85% lower rate of major cardiovascular events among patients with FH during a mean of 2 years of treatment with mipomersen compared with the rate of events during 2 years before initiation of treatment, but additional studies are required to verify these findings.¹⁶

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that lowers the concentrations of LDL and apo B by decreasing production of VLDL, the precursor of LDL.¹² MTP is expressed in the small intestine and liver, where it facilitates lipidation of apo B-48 in the enterocyte and apo B-100 in the hepatocyte during the formation of chylomicrons and VLDL particles, respectively. Lomitapide is an orally administered medication that is given at an initial dose of 5 mg daily with titration possibly up to a dose of 60 mg daily, as tolerated. The concentrations of LDL-C and apo B may be lowered by a mean of 40% in a dose-dependent manner, but lower doses are less efficacious than higher doses. Statistically significant decreases in lipoprotein(a) have not been demonstrated. Because the drug inhibits MTP in the small bowel and contributes to fat malabsorption and possible steatorrhea, it is necessary for patients taking this drug to consume a diet that is very low in fat with supplementation with fat-soluble vitamins and essential fatty acids. In addition to diarrhea, steatorrhea, and abdominal discomfort, toxicity of lomitapide can include hepatic transaminase elevations, hepatic steatosis, and intestinal steatosis, as well as deficiencies of essential fatty acids and fat-soluble vitamins.

Anti-PCSK9 Antibodies

The newest class of LDL-C-lowering drugs are the anti-PCSK9 antibody agents, two of which were approved by the FDA in mid-2015 for treatment of patients with FH or coronary artery disease (or both) who require additional LDL-C lowering.¹⁷ PCSK9 was discovered only about 12–13 years ago, but the rapid progress of development of this therapeutic approach led to the clinical availability of alirocumab and evolocumab in a very short time span. PCSK9 is coordinately upregulated in conjunction with factors that upregulate the LDL receptor.¹⁸ Since PCSK9 sabotages the LDL-receptor by binding to it and targeting it for lysosomal degradation, upregulation of PCSK9 attenuates the LDL-C-lowering efficacy of all treatments that upregulate expression of the LDL receptor, including a low-saturated-fat, low-cholesterol diet, statins, ezetimibe, bile-acid sequestrants, and, to some extent, niacin.

Alirocumab and evolocumab bind to and block the adverse effect of PCSK9 on hepatic LDL receptor degradation, resulting in a dramatic mean 50%–60% reduction in the plasma LDL-C concentration beyond the baseline LDL-C concentration achieved in response to treatment with maximum doses of statins and other medications.^19,20 Side effects have been similar between patients treated with placebo and active drugs.

The drugs have no efficacy in patients with homozygous FH who have no residual LDL receptor activity, but evolocumab is FDA approved for treatment of patients with homozygous FH on the basis of data demonstrating an ∼30% reduction in LDL-C in homozygous FH patients who have sufficient residual LDL receptor activity that can be upregulated in response to blocking PCSK9.²¹

The results of preliminary analyses submitted to the FDA before FDA approval demonstrated an ∼50% lower rate of cardiovascular events after 1–1.5 years of placebo-controlled or uncontrolled treatment with these drugs.^22,23 Large blinded, placebo-controlled clinical intervention trials designed to verify the apparent cardiovascular benefits of these drugs are in progress. It is possible that data from one or more of these trials may be available in early 2017 if the studies are terminated early due to positive outcomes.

LDL/Lipoprotein Apheresis

LDL apheresis is an extra-corporeal procedure in which LDL and other apo B-containing lipoproteins are removed from plasma by a variety of techniques that include adsorption of apo B to columns containing dextran sulfate or precipitation of LDL under conditions of acidic heparinization.²⁴ The concentrations of LDL cholesterol and apo B can be acutely lowered by 75%–85% during a 3–4-hr procedure, with somewhat lower reductions in lipoprotein(a). Since the procedure removes all atherogenic lipoproteins in addition to LDL, the procedure is also referred to as lipoprotein apheresis.

The procedure is FDA approved for treatment of patients with coronary artery disease and LDL-cholesterol concentration >160 mg/dL during maximal tolerated LDL-cholesterol-lowering drug therapy, or >300 mg/dL in patients without coronary artery disease. Most individuals who meet these conditions have FH. The treatment is generally performed biweekly for patients with heterozygous FH and weekly for patients with homozygous FH. Access to centers that provide LDL/lipoprotein apheresis is limited in the United States and many other countries, with only about 400–500 individuals undergoing this treatment modality in the United States. The results of one recent study demonstrated that treatment with alirocumab, an anti-PCSK9 therapy, may allow a reduction in the frequency or termination of LDL/lipoprotein apheresis treatments in more than 2 out of 3 of patients.²⁵

Liver Transplantation

Another therapy for homozygous FH is liver transplantation, especially if the patient cannot tolerate lipoprotein apheresis. Although this is a therapy that essentially reverses the LDL receptor deficiency, it is not readily available and carries the risks of transplant surgery and immunosuppression.

Summary

The current era is a fabulous time for management of patients with FH. Until the first statin was FDA approved for treatment of hypercholesterolemia in 1987, the mainstay of treatment for patients with FH was immediate-release niacin in combination with bile-acid sequestrants. This “fire and sand” regimen was associated with challenging side effects and was minimally efficacious, which allowed many patients with FH to continue to suffer early cardiovascular morbidity and mortality. The availability of statins markedly improved the prognosis for patients with FH, and increased the mean life expectancy of homozygous FH patients from 19 to 32 years, but adjunctive therapies were still needed to improve a persistently grim prognosis.

As of 2015, with the approval of two medications that block PCSK9, our ability to achieve excellent LDL-C lowering to <70 mg/dL in patients with FH is extraordinary in comparison to the situation 30 years ago. Aggressive multidrug regimens are required for many patients, and LDL/lipoprotein apheresis is still needed for a small percentage of FH patients, but the clinical availability of seven classes of LDL-lowering medications has made it possible for clinicians to achieve LDL-cholesterol goals that were unattainable in the past.

As an example, one of our patients with homozygous FH has been able to lower his LDL-cholesterol concentration from a baseline of 750 mg/dL as a child to 100–110 mg/dL in response to a 6-drug LDL-lowering regimen, comprising an 87% reduction in his LDL-cholesterol concentration.

Conclusion: Optimism for Patients with FH

Our current ability to dramatically lower the LDL-cholesterol concentration in patients with FH is anticipated to markedly reduce or possibly eliminate the extreme cardiovascular risk associated with this disorder. To accomplish this goal, early diagnosis and treatment of the disorder is essential, in combination with clinicians taking advantage of all of the available treatment modalities to lower the burden of atherogenic lipoproteins to a level that will prevent development of cardiovascular morbidity and mortality. In this current era, we as clinicians now have the capability and responsibility to convert FH from a diagnosis with a previously grim prognosis to a condition that we can potentially neutralize in the majority of patients.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

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