ABSTRACT

Genetic disorders resulting in familial hypercholesterolemia (FH) include autosomal dominant hypercholesterolemia (ADH), polygenic hypercholesterolemia, as well as other rare conditions such as autosomal recessive hypercholesterolemia (ARH). All of these disorders cause elevations in low-density lipoprotein (LDL)-cholesterol (LDL-C) and, as a result, greatly increase the risk of cardiovascular disease (CVD). Genetic loci involved in ADH include the LDLR, which codes for the LDL receptor (LDLR), APOB, which codes for apolipoprotein B-100 (apoB-100), the major protein component of LDL, PCSK9, which codes for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), the low abundance circulatory protein that terminates the lifecycle of the LDLR, and apolipoprotein E (APOE), which synthesizes the main protein of triglyceride rich lipoproteins. Importantly, a large percentage of people with the severe hypercholesterolemic phenotype do not possess a readily identifiable gene defect and many likely have polygenic hypercholesterolemia. Thus, identification of a specific genetic pathologic variant is not a necessary condition for the diagnosis of a genetic hypercholesterolemia. Several formal diagnostic criteria exist for FH and include lipid levels, family history, personal history, physical exam findings, and genetic testing. As all individuals with severe hypercholesterolemia are at high risk for CVD, treatment is centered on dietary and lifestyle modifications and early institution of lipid-lowering pharmacotherapy. Treatment should initially be statin-based, but most patients require adjunctive medications such as ezetimibe and PCSK9 blocking monoclonal antibodies. Three large cardiovascular outcome trials have shown a reduction in atherosclerotic CVD when ezetimibe or PCSK9 blocking monoclonal antibodies were added to a background of statin therapy and consequently have assisted in shaping international guidelines and consensus recommendations. Novel therapeutics recently developed, include: inclisiran – a small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits PCSK9 production (approved in the European Union only thus far), bempedoic acid – an inhibitor of adenosine triphosphate (ATP)-citrate lyase (FDA approved for heterozygous FH and patients with prior CVD and elevated LDL-C), and evinacumab – a fully human monoclonal antibody inhibiting angiopoietin-like 3 (ANGPTL3) (FDA approved for homozygous FH only). Patients with extreme and unresponsive elevations in LDL-C will require more aggressive therapies such as lipoprotein apheresis and agents for the treatment of severe hypercholesterolemia such as microsomal triglyceride transfer protein (MTP) inhibitors and evinacumab. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Genetic disorders resulting in familial hypercholesterolemia (FH) consist of autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH), and polygenic hypercholesterolemia. The genetic architecture of FH is more complex than previously recognized and in fact is now believed to be associated with at least nine different genes with thousands of variants, the details of which are beyond the scope of this chapter. But briefly, the term “autosomal dominant hypercholesterolemia” refers to those patients with dominantly inherited severe hypercholesterolemia – low-density lipoprotein (LDL)-cholesterol (LDL-C) greater than 190 mg/dL, who likely harbor mutations in genes regulating serum LDL levels. Historically, the more common causes of ADH include “classic” FH, which is a codominant disorder involving aberrations in the LDL receptor (LDLR), as well as other codominant forms of “nonclassical” FH, which involve defects in two other genes that regulate plasma clearance of LDL, apolipoprotein B (APOB), which synthesizes the main protein of LDL (a ligand for the LDLR), and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), which synthesizes a low abundance circulatory protein that limits the LDLR lifespan (1,2). Autosomal dominant forms of ADH previously include mutations in apolipoprotein E (APOE), which synthesizes the main protein of triglyceride rich lipoproteins and signal transducing adaptor family member 1 (STAP1), whose function in cholesterol homeostasis remains largely unknown (2,3). However, recent data have determined that mutations in STAP1 are not a causative factor in FH (4-7). An autosomal recessive form of FH, ARH, is very rare and results from pathogenic variants in LDLR accessory protein 1 (LDL-RAP1). Other forms may be due to defects in lysosomal acid lipase (LIPA), ATP- binding cassette sub-family G member 5 and 8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1) (2,8). Finally, a common form of FH is attributable to multiple variations in several genes each with minor effects on cholesterol regulation (more than 50 loci identified, as opposed to a single large effect as seen in the textbook version of FH). Polygenic causes are relatively common and likely explain many of the patients who are genotype negative. In fact, up to 50% of patients referred to lipid clinics for possible or probable HeFH have a polygenic basis (2). Additionally, only approximately 2% of patients with an LDL >190 mg/dL and no additional clinical or family history compatible with FH have a pathogenic variant in one of the FH genes (9,10). Thus, having an elevated LDL-C does not necessarily indicate that the patient has ADH due to a pathogenic variation in the LDLR, APOB, PCSK9, or APOE genes. All forms of FH result in very high levels of LDL-C and increase the risk of early and accelerated coronary artery disease (CAD) (8). Yet, FH remains vastly underdiagnosed and thus, undertreated, representing an extraordinary missed opportunity for maintenance of cardiovascular healthy and prevention of cardiovascular events. It has been estimated that less than 10% of the patients in the US with FH have been diagnosed (11,12). This chapter will largely focus on the canonical forms of FH involving the five traditional genetic loci described above.

GENETICS

The LDLR is an 893-amino acid cell surface glycoprotein that binds and internalizes LDL particles, primarily in the liver. Mutations in LDLR (i.e., “classic” FH) give rise to nearly 90% of cases of clinical ADH (13). Over 2000 such mutations in LDLR have been identified, including deletions, insertions, missense, copy number variants, and nonsense mutations (2). FH patients can be homozygous (traditionally with a prevalence thought to be 1 in 1,000,000 but based on contemporary genetic studies, the prevalence is thought to be closer to 1 in 300,000), carrying mutations in both alleles encoding for LDLR, or heterozygous (traditionally with a prevalence thought to be 1 in 500, with newer data suggesting as frequent as 1 in 200), possessing mutations in only one allele (2,14). Homozygous FH (HoFH) should be suspected when LDL-C exceeds 400 mg/dL, whereas heterozygous FH (HeFH) should be suspected when LDL-C is greater than 190 mg/dL in adults and 160 mg/dL in children (8). Patients with HoFH can be true FH homozygotes, with two identical mutations in each allele, versus compound heterozygotes, with a different mutation in each allele. In addition, FH can result in elevated levels of lipoprotein(a) (Lp[a]) through an unclear mechanism, not necessarily linked to the dysfunctional LDLR pathway (15-19). Elevated Lp(a), which is composed of 30-45% cholesterol by mass and reported as part of the LDL-C laboratory measurement, amplifies the already increased risk of incident CAD seen in those with FH (19). It is also important to be aware of “founder effects” in some populations. Founder effects influencing the type and frequency of mutations causing FH are seen among Afrikaners, French Canadians, Ashkenazi Jews, Christian Lebanese, and some Tunisian groups. Slimane et al. estimated the prevalence of individuals with HoFH and HeFH in Tunisia to be 1:125,000 and 1:165, respectively (20).

“Nonclassical” FH, which phenotypically resembles classic FH in presentation and severity, involves dominantly inherited gene defects in APOB, PCSK9, and APOE, which code for proteins that modulate ligand-LDL/LDL-like receptor interaction (2,21,22). ApoB is the major protein constituent of LDL and acts as a ligand for LDLR. Mutations in ApoB (most commonly a single base change at a position near amino-acid 3,500) block the binding of LDL containing the apoB-100 to LDLR, resulting in severely elevated levels of LDL-C. This condition was originally defined as “familial defective APOB-100” or FDAB (23). PCSK9, on the other hand, is a circulating protein that terminates the lifecycle of LDLR by binding to it and targeting it to lysosomal degradation. Gain-of-function (GOF) mutations in PCSK9 lead to a FH phenotype, whereas loss-of-function (LOF) mutations lead to lower LDL-C and protection from coronary atherosclerotic events (24,25). Absence of circulating PCSK9 has been reported in a few subjects, who were reportedly healthy and had LDL levels around 20 mg/dL (26,27). Collectively, these observations spurred a frenzy of targeted research that led to the development and FDA approval of therapeutic antibodies against PCSK9 to reduce LDL levels in individuals with atherosclerotic cardiovascular disease (ASCVD) and/or in FH. Mutations in ApoE (an in-frame three base-pair deletion at position 167 in exon 4) block the binding of triglyceride rich lipoproteins (i.e., chylomicrons, chylomicron remnants, very low-density lipoprotein [VLDL-C], intermediate-density lipoprotein [IDL-C]) to the E receptor (belongs to the LDLR superfamily), and limits clearance of these particles from plasma (28). The prevalence of ADH resulting from mutations in APOB, PCSK9, and APOE has been difficult to estimate, but it is agreed that these are 5-10%, <1%, and <<1% respectively (2).

Finally, an additional ultra-rare recessive genetic disorder causing hypercholesterolemia bears mentioning. It involves a homozygous deletion mutation in the gene CYP7A1. This gene codes for the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. The mutation results in loss of enzymatic function and high levels of LDL-C, and was first identified in three homozygotes within a single kindred of English and Celtic descent (29). There are a number of other rare recessive genetic disorders that are associated with hypercholesterolemia, see table 1 below and other Endotext chapters on these rare genetic disorders.

An important practical point is that 30-50% of people with the FH phenotype have no readily identifiable defects in any of the genes that have been mentioned here; thus, diagnosing an individual with the FH phenotype does not necessarily mean the presence of a monogenic defect in the LDLR pathway (30). The genetic confirmation for FH-causing mutations in ADH varies considerably (2,10). The rate of positive genetics is related to clinical criteria - in patients with definite FH based on clinical criteria 60-80% are positive whereas in patients with possible FH based on clinical criteria only 21-44% are positive (31). Additionally, the LDL-C level is crucial. When LDL-C is very high (i.e., >310 mg/dL), the frequency of monogenic pathogenic variants is as high as 92% (32). In patients without an identifiable pathologic genetic variant the etiology may be due to an as-yet-unidentified genetic error or to polygenic, epigenetic, or non-genetic factors, including co-morbid and environmental modifiers. For those without a mutation, an elevated LDL-C still confers elevated cardiovascular disease (CVD) risk. However, for any given LDL-C strata, those with a causal mutation compared to those without have higher risk for CVD, likely due to lifelong exposure to high LDL-C (10,33). In addition, unintended consequences of genetic testing (i.e., genetic discrimination for life or long-term care insurance and increased expense) must be taken into account. For these reasons, genetic testing should not be mandated, but should involve a shared-decision making model between patient and provider, encompassing benefits and risks of genetic testing, as well as patient values and preferences (34). On the other hand, others advocate for routine genetic testing citing as rationale 1) facilitate a definitive diagnosis; 2) identify pathogenic variants with higher cardiovascular risk and therefore needing more aggressive treatment; 3) increase initiation of and adherence to therapy; 4) facilitate insurance approval for novel lipid-lowering therapies; and 5) cascade testing of first-degree relatives (25). Cascade screening on the basis of LDL-C alone (i.e., ≥190 mg/dL) has low sensitivity and specificity, however, identification of a pathogenic variant with genetic testing followed by cascade screening results in very high sensitivity and specificity. This is likely due to missed diagnoses of FH with reduced penetrance where LDL-C is <190 mg/dL (31). Nonetheless, the reduced costs and more widespread availability of genetic testing warrant performance of this test to obtain information that can help the physician familiarize with genotype-phenotype correlations and identify subjects that can be studied for the discovery of novel pathways leading to severe hypercholesterolemia. It must be noted that the FDA does not mention genetic testing as a measure to define FH (either heterozygous or homozygous).

PATHOPHYSIOLOGY

Most circulating LDL particles end up in the liver. The LDLR pathway is the predominant method for LDL uptake (35,36). ApoB binds to a specific binding site on LDLR and the receptor-ligand complex is subsequently internalized from clathrin-coated pits on the cell membrane. The receptor-ligand complex undergoes endocytosis and is targeted to the lysosome, where LDL is released for degradation while the LDLR is recycled back to the cell surface approximately 100-150 times in its 24 hour life cycle (2). PCSK9 terminates LDLR lifespan by disallowing its recycling, thus providing a physiologic mechanism of protein removal much different from, and stronger than, that caused by inducible degrader of LDL, an E3 ubiquitin ligase (24,37). There are other nonspecific and constitutively active pathways of LDL-C clearance as well (35,38). In HeFH, though transport through the LDLR pathway is reduced by 50%, LDL-C clearance is doubled through these other, non-LDLR pathways. The same holds true for HoFH, where despite a near-absolute reduction in LDLR transport, total LDL-C clearance via non-specific pathways is increased by 4-fold (39). Excess LDL-C, which accumulates in liver cells, is then re-exported via the apoB system back into the plasma, secreted into bile unchanged, or transformed into bile acids. This increased production of LDL adds to inefficient clearance via LDLR to cause elevated serum LDL levels typical of the FH phenotype (40).

ADH can thus be further classified into subtypes 1, 2, and 3, based on which protein of the LDLR pathway is causative (Figure 1). ADH-1 comprises mutations within LDLR, the canonical form of FH. There are six major classes of ADH-1 (see table 2 below), based on the type of mutation. These include those that: inhibit synthesis of LDLR; impede exit of mature LDLR from the endoplasmic reticulum; affect the binding site of LDLR to apoB-100; prevent the ligand-receptor interaction; prevent endocytosis of the LDLR-apoB-100 complex; or inhibit recycling of LDLR to the cell surface for further rounds of lipid uptake (not shown). ADH-2 comprises mutations of APOB that block the association of apoB-100 to LDLR. ADH-3 is due to GOF mutations of PCSK9, which reduce LDLR recycling and accelerate its lysosomal degradation (12). Some authors have suggested that mutations that affect binding of apoB-100 to LDLR carry a less severe phenotype than those that affect LDLR directly (41-45).

FIGURE 1

(22): ADH-1 comprises mutations within LDLR. There are six major classes of ADH-1, affecting: a) synthesis of LDLR; b) exit of mature LDLR from the endoplasmic reticulum; c) binding site of LDLR to apoB-100; d) endocytosis of LDLR-apoB-100 complex; and recycling of LDLR to the cell surface (not shown). ADH-2 comprises mutations in apoB that block the association of apoB-100 to LDLR. ADH-3 is due to GOF mutations of PCSK9, which reduce LDLR recycling and accelerate its lysosomal degradation. Adapted from Calandra et al. J. Lipid Research 2011; 52: 1885-926.

CLINICAL MANIFESTATIONS

DIAGNOSIS

FH, despite its different underlying gene abnormalities, leads to severe hypercholesterolemia and a distinct FH phenotype with markedly increased risk of developing CAD. In general, there are five major clinical criteria for diagnosing FH (see table 3): a family history of early CAD (less than age 55 in a first-degree relative in men, and less than age 65 in women), early CAD in the index case, elevated LDL-C (greater than 190 mg/dL), tendon xanthomas (especially in the Achilles and finger extensor tendons), and corneal arcus (which is highly specific in younger patients, but overall an insensitive finding). Mutations in any of the aforementioned genes of the LDLR pathway, when they are identified, are diagnostic.

As has been mentioned in other chapters of this text, when evaluating a patient suspected of having FH, it is critical to rule out secondary causes of hypercholesterolemia, such as hypothyroidism, nephrotic syndrome, and liver disease. Another extremely rare cause of non-FH has been described, involving autoantibodies to LDLR that inhibit receptor-mediated binding and catabolism of LDL-C (73).

There are three sets of statistically validated criteria that are most commonly used in the diagnosis of FH: the Dutch Lipid Network criteria, Simon Broome Register criteria, and Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria (74,75). These are summarized in Table 4, below (76).

Unlike MEDPED criteria, which use only lipid levels, the Simon Broome and Dutch criteria also use family history, personal history, physical exam findings, and genetic testing to establish an FH diagnosis. Again, however, it should be emphasized that FH should be diagnosed phenotypically, as opposed to genetically—most FH patients are genotype-negative and do not possess a clear genetic substrate for their hyperlipidemic phenotype, but they clearly warrant aggressive intervention.

It is important to note that in the modern era of earlier recognition, wide-spread statin use and possibly improved dietary messages, it is often difficult to make a definitive or probable diagnosis of FH using clinical criteria (i.e., treatment reduces the development of xanthomas and corneal arcus and reduces or delays the occurrence of ASCVD events in patients and relatives). Similarly, it is often very difficult to know the before treatment LDL-C levels (31).

While genetic screening is not required for clinical management, lipid screening in family members should be undertaken in all individuals by age 20, starting as early as age 2 (42). Cascade screening—i.e., lipid screening of first-degree relatives of the proband—is infrequently employed, but is recommended as the most economical method of identifying new cases of FH (43). It is the responsibility of the examining clinician to attempt identification of other cases when making the diagnosis of FH in any given patient.

A potential novel solution to the underdiagnosis and undertreatment issues that plague the FH community, lies in leveraging health information technology. The FIND FH study demonstrated the use of a machine learning algorithm can successfully utilize medical profiles within the electronic health record to consistently identify individuals with probable FH (77). This new approach possesses the promise of identifying FH patients on a national scale and will hopefully lead to increased initiation of effective preventive therapies and at an earlier time-point as well.

TREATMENT

Treatment of Patients with Heterozygous Familial Hypercholesterolemia

As with almost all metabolic disorder we should encourage the patient to follow a lifestyle that will reduce disease manifestations. However, lifestyle changes are very rarely sufficient to lower LDL-C levels to the desired range in patients with FH and therefore cholesterol lowering drugs will be required (see figure 2 and tables 6 and 7) (for detailed information on cholesterol lowering drugs see the chapter on cholesterol lowering drugs (85). In patients with HeFH, statins are a mainstay of treatment, despite the dearth of randomized clinical trials of statin efficacy in this special population. Statins are FDA approved for use in pediatric FH patients beginning at age 8-10 years for HeFH and in the first year of life or at initial diagnosis for HoFH (46,68,83,86-90). Data from longitudinal observational studies suggest statin initiation in childhood is both safe and effective, reducing LDL-C burden and corresponding atherosclerosis rates over follow-up of up to 20 years (46,91). The major early statin trials (4S and WOSCOPS) likely had study populations that were enriched with FH patients, given that mean baseline LDL-C ranged from 189 to 216 mg/dL (92,93). Patients should be treated with atorvastatin 40-80 mg per day or rosuvastatin 20-40 mg per day (i.e., high-intensity statin therapy). As monotherapy, statins can reduce LDL-C by up to 60% in HeFH patients but typically display a blunted response (10-25%) in HoFH patients depending on LDLR functionality (68,94). The vast majority of patients, however, require additional pharmacotherapy. When intensive statin therapy does not result in an LDL-C level in the desired range additional therapy should be added. Given that ezetimibe is now generic, relatively inexpensive, well tolerated, and has evidence for ASCVD risk reduction in a large cardiovascular outcome trial, this is frequently the next drug used (95). One can anticipate that ezetimibe 10 mg per day added to intensive statin therapy will result in an approximate 20% further reduction in LDL-C. If this is not sufficient one can then use a PCSK9i monoclonal antibody to achieve the desired cholesterol goal. Adding a PCSK9i monoclonal antibody will result in a further 50-60% decrease in LDL-C levels and in most patients will result in LDL-C levels in the desired range. In some instances, if the LDL-C level is far from goal (>25%) on intensive statin therapy one can skip treating with ezetimibe and proceed directly to adding a PCSK9i monoclonal antibody. Bempedoic acid (discussed in more detail below) is an acceptable third- or fourth-line add-on agent if additional LDL-C lowering is needed. In certain instances, bile resin binders may be useful in the treatment of FH (for example pregnant and lactating patients).

FIGURE 2.

Approach to the Pharmacologic Treatment of Patients with Heterozygous Familial Hypercholesterolemia

PCSK9 inhibitors consist of two therapeutic modalities, 1) monoclonal antibodies (alirocumab and evolocumab) that work extracellularly to sequester the PCSK9 protein, and 2) inclisiran, a novel, small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits mRNA translation and intracellular production of PCSK9 by the liver.(96)

The effect of PCSK9i monoclonal antibodies in patients with HeFH has been extensively studied and consistently demonstrate potent LDL-C lowering on the order of 50-60% (58,97-111). An analysis of the ODYSSEY trials (FH I, FH II, LONG TERM, and HIGH FH) evaluated alirocumab use (75 or 150 mg subcutaneously every 14 days) in 1,257 HeFH patients. The primary endpoint was LDL-C at 24 weeks; alirocumab resulted in a more than 55% reduction in LDL-C compared with placebo (107). In another trial, alirocumab 150 mg every 14 days in 62 apheresis patients reduced the primary endpoint, rate of apheresis treatments over 12 weeks, by 75%, with 63.4% of patients completely discontinuing apheresis treatments due to well controlled LDL-C values (106). The RUTHERFORD-2 trial, evaluated more than 300 patients with HeFH randomized to evolocumab (140 mg subcutaneously every 2 weeks or 420 mg subcutaneously monthly) versus placebo. At both dosing regimens, evolocumab resulted in significantly reduced LDL-C at 12 weeks compared with placebo (>60%) (58). In all trials, PCSK9i monoclonal antibodies were well tolerated, with most demonstrating treatment-emergent adverse events (TEAEs) similar to placebo. Clinically, the most common adverse events include: injection site reactions, mild cold or flu-like symptoms, nasopharyngitis, and myalgias (112). Thus, PCSK9i monoclonal antibodies are very effective at lowering LDL cholesterol levels and safe in HeFH patients.

Additionally, there are two cardiovascular outcomes trials that evaluated the FDA approved monoclonal antibodies targeting PCSK9. The FOURIER trial evaluated almost 28,000 subjects with stable vascular disease (CAD, stroke, peripheral arterial disease) on optimized statin therapy and randomized them to either placebo or evolocumab. Evolocumab therapy was associated with a 60% reduction in LDL-C and a 15% reduction in the primary 5-point major adverse cardiovascular outcome endpoint (113). ODYSSEY OUTCOMES enrolled approximately 18,000 subjects with recent acute coronary syndrome (1-12 months prior to enrollment in the trial) who were on high-intensity statin therapy at baseline and randomized them to placebo or alirocumab. Alirocumab was also associated with a 15% reduction in the primary outcome, in this case a 4-point composite of major adverse cardiovascular events (114). Major guidelines, consensus documents, and expert recommendations suggest consideration of a PCSK9 inhibitor (in addition to background statin +/- ezetimibe therapy) in high-risk patients with established ASCVD and/or in patients with severe hypercholesterolemia when LDL-C values exceed 70 or 100 mg/dL respectively (81,83,84,115-118). Both monoclonal antibodies have an FDA labeled indication for ASCVD risk reduction in patients with established ASCVD.

Inclisiran has been thoroughly studied in the ORION clinical development program, a series of phase 1 to 3 trials designed to investigate the pharmacokinetics, pharmacodynamics, optimal dose, efficacy, and safety of inclisiran in specific populations (96). ORION-9 was a phase 3, randomized, double-blinded, placebo-controlled trial evaluating use of inclisiran 300 mg given subcutaneously on days 1, 90, 270, and 540, in 482 HeFH patients with baseline LDL-C of ≥100 mg/dL(119). Treatment with inclisiran produced a placebo-corrected LDL-C reduction of 47.9% (P<0.001) at day 510. Response based on genotype was as expected, with LDL-C reductions of 41.2% to 59.2% for all except PCSK9 GOF variants which were associated with dramatic LDL-C reduction of 89.7%. Pre-specified exploratory cardiovascular event (CV death, cardiac arrest, non-fatal MI, or non-fatal stroke) rates were comparable in both treatment groups (4.1% inclisiran vs. 4.2% placebo). Inclisiran was tolerated well during the trial with adverse events similar between treatment groups, with most adverse reactions mild to moderate in nature. The most common adverse event was injection site reactions, which was 10-fold higher in the inclisiran group (17%) compared to placebo (1.7%), however, 90% of these were graded as mild severity. Future studies will evaluate inclisiran in an adolescent HeFH population in the ORION-16 trial (120). Inclisiran remains experimental in the US but was approved for clinical use in the European Union (EU) in December 2020 (121). Though PCSK9 inhibition by monoclonal antibodies and inclisiran are comparable in LDL-C reducing capacity, there are important differences to acknowledge 1) inclisiran has a long biological half-life allowing for twice yearly dosing and possible medication adherence advantages, 2) PCSK9i monoclonal antibodies are administered by patients in their home and inclisiran is to be administered by a healthcare professional in a healthcare setting, and 3) while PCSK9i monoclonal antibodies have robust data proving reduction in ASCVD events, clinical outcome trials with inclisiran are still in progress.

Bempedoic acid, a novel inhibitor of adenosine triphosphate (ATP)-citrate lyase (ACL), an enzyme upstream from 3–hydroxy–3–methylglutaryl coenzyme A (HMG–CoA) in the cholesterol synthesis pathway, is the newest orally administered lipid-lowering therapy (122). Bempedoic acid is a prodrug, that is converted into its active form (bempedoyl-CoA) by very long-chain acyl-CoA synthetase 1 (ACSVL1), which is expressed in hepatocytes but is undetectable in muscle. Development of this agent was designed to circumvent the myotoxicity commonly associated with historical lipid-lowering therapies, primarily statins. Bempedoic acid was FDA approved on February 21, 2020 for use in patients with established ASCVD and/or HeFH who require additional LDL-C lowering as an adjunct to dietary intervention and maximally tolerated statin therapy (123). Bempedoic acid was evaluated in over 3600 patients in the phase 3 CLEAR program trials, of which, only 3.7% were HeFH patients (122). A pooled analysis from two phase 3 trials, CLEAR Harmony and CLEAR Wisdom, demonstrated a similarly modest placebo-corrected LDL-C reduction at 12 weeks of bempedoic acid treatment in the HeFH cohort (22.3%) as compared to the overall population (18.3%) (124). Overall bempedoic acid was well tolerated in the phase 3 trials but occurrence of TEAEs was higher in the HeFH cohort compared to those without HeFH but was not increased with bempedoic acid versus placebo. In a real-world analysis of bempedoic acid, which was enriched in patients with HeFH (64%) and statin intolerance (74%), the drug was associated with clinically meaningful LDL-C lowering (mean reductions 20.3% to 36.7%), but high rates of TEAEs (50%) and drug discontinuations (35.9%) (unpublished observations – manuscript under submission).

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