Genetic testing for FH aims to provide an underlying molecular diagnosis and offer valuable prognostic information. It is currently advocated globally, including by the American College of Cardiology, International Societies of Atherosclerosis, and European Societies of Atherosclerosis [12]. Although genetic testing is performed extensively at the population level in European countries, the CASCADE Registry results demonstrated that genetic testing for FH was underutilized in the United States, with only 4% of participants with a clinical diagnosis of FH reporting genetic testing [31]. Mutations in the LDLRare by far the most frequent cause of FH [32], but genes encoding apoB and PCSK9 are also associated with FH [7]. Mutations in one of these three genes account for 60–80% of cases of FH [3]. In those with genetically confirmed FH, the vast majority (90–95%) of identified mutations are found in the LDLR gene, 5–10% in the apoB gene, and approximately 1% in the PCSK9 gene (Fig. 1) [6, 7, 8].

The utility of the established clinical criteria for diagnosing FH has been challenged previously due to the phenotypic heterogeneity of these patients. For example, a study of the Dutch Lipid Clinic network database identified 2400 patients as having FH using established clinical diagnostic criteria, but showed significantly different clinical and laboratory profiles between those with versus without a known LDLR mutation [33]. In addition, the limitations of employing specific LDL-C cutpoints to identify individuals with pathogenic FH mutations have been highlighted. A whole-exome sequencing analysis from a large cohort, including participants from seven case-control studies (CAD case subjects and CAD-free control subjects) and five prospective cohort studies, demonstrated that 45% of those with LDL-C levels $\ge$190 mg/dL and 27% with LDL-C level 130 mg/dL had a pathogenic variant [34]. Thus, one purpose of FH genetic testing is to identify individuals who may not have been diagnosed with FH based on their lipid levels, clinical and physical characteristics, and/or family history [12].

Genetic testing is also valuable for providing prognostic information. In a study including 26,025 participants, compared with a reference group with LDL-C 130 mg/dL and no mutation, there was a 6-fold higher risk for CAD in participants with LDL-C $\ge$190 mg/dL and no FH mutation and a 22-fold higher risk in those with both LDL-C $\ge$190 mg/dL and an FH mutation [34]. Similarly, a study including 409 FH patients participating in the Simon Broome British Heart Foundation study showed that compared with those with no mutation, the participants with LDLR mutation had 70% higher odds of CAD, and those with PCSK9 mutation had 20-fold higher odds of CAD [35]. Another study examined the effect of monogenic and polygenic causes of hypercholesterolemia on the incidence of early ASCVD in patients with clinically diagnosed FH and demonstrated that a monogenic cause of FH was associated with a significantly increased risk of CV disease (CVD) (hazard ratio (HR): 1.96; 95% confidence interval (CI): 1.24–3.00; p = 0.004), while patients with polygenic FH did not differ significantly from those with no identified genetic cause of FH [36]. These studies suggest that those with FH-causing mutations may have a higher average lifetime LDL-C exposure than those without a mutation, which might contribute to higher ASCVD risk among mutation carriers. FH genetic testing should be followed by pre and post-test genetic counseling to ensure that patients are informed of the advantages, disadvantages, and familial ramifications of genetic testing [12].

Considering the autosomal dominant pattern of FH, it is essential to identify other family members with FH. Cascade testing is a mandatory part of the approach in which LDL-C measurement, genetic testing, or both are performed on all first-degree relatives of FH patients [7]. It has been demonstrated that cascade testing leads to earlier FH detection and is a cost-effective strategy for reducing CAD, myocardial infarction, and death [37, 38]. An analysis of the SAFEHEART registry revealed that cascade testing prevented 847 coronary events and 203 deaths in 9000 FH patients over a 10-year follow-up period, resulting in an additional 767 quality-adjusted life years [38]. In addition, the data from the United States population using a simulation model demonstrated that cascade genetic testing for FH was cost-effective if started before age 40 in first-degree relatives and before age 15 in second-degree relatives [39]. Not only is cascade testing cost-effective, but it is also crucial because FH is eminently treatable [40]. When detected and treated at a young enough age, the risk of ASCVD can be drastically reduced, possibly to average levels. Although the Centers for Disease Control and Prevention have given cascade testing of relatives of patients with FH the Tier 1 classification, there are currently no systematic cascade testing programs in the United States [41]. In addition to reluctance on the part of family members to accept genetic testing, the lack of trained healthcare professionals to perform the necessary pedigree construction and the logistics of contacting relatives to obtain informed consent for genetic testing and a blood sample, are the primary obstacles to the cascade testing [42].

Although patients with FH are regarded to be at high ASCVD risk, the evidence indicates that their CV prognosis is quite heterogeneous. Despite substantial research into the factors influencing ASCVD risk in the FH population, precise risk prediction remains unclear [43]. There are several risk calculators explicitly designed for the FH population [44, 45, 46]. The Montreal-FH-SCORE incorporates five clinical variables, including age, sex, smoking, hypertension, and HDL-C, and has been validated in retrospective cohorts [47]. The SAFEHEART risk equation, which constitutes traditional risk factors such as age, sex, smoking, hypertension, body mass index, a history of ASCVD, and levels of LDL-C and lipoprotein (a) (Lp(a)), has also been externally validated but included both primary and secondary CV prevention populations [48]. Recently, a new score called the FH-Risk-Score was developed to predict incident ASCVD events in a large multinational prospective cohort of patients with FH without prior history of ASCVD that incorporates seven clinical variables, including age, sex, hypertension, smoking, LDL-C, HDL-C, and Lp(a) [46]. It was found to be a better predictor of future ASCVD events than the SAFEHEART risk equation for FH patients with no prior history of ASCVD [46]. To improve CV risk stratification in FH, the detection of subclinical atherosclerosis utilizing coronary artery calcium, carotid intima-media thickness, and coronary computed tomographic angiography has also been proposed [49, 50].

The treatment of FH begins with the maximally tolerated dose of a high-intensity statin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [56]. These drugs interfere with the rate-limiting step in cholesterol biosynthesis by antagonizing HMG-CoA reductase, thus decreasing intrahepatic cholesterol and increasing LDLR expression, which lowers circulating LDL-C through increased hepatic uptake. Statin monotherapy has been shown to reduce LDL-C by 50–60% in HeFH [57] and 10–25% in HoFH [13], along with a reduction in CV events and mortality [52, 53]. Despite pharmacodynamic concerns for statin efficacy in receptor-negative HoFH, these patients do respond to statin therapy, although to a lesser extent (23.5% LDL-C reduction in those with residual LDLR activity versus 14% in those with two null LDLR mutations) [58]. Statins have also proven safe and effective in children [59], with current recommendations to start low and gradually increase the dose to reach the LDL-C goal [55]. However, adequate lipid lowering is rarely achieved with statin monotherapy in adults with FH, thus requiring a combination with drugs utilizing alternate mechanisms of action.

Ezetimibe is the most commonly prescribed LDL-C-lowering drug after statins. It acts by inhibiting the Niemann-Pick C1-Like 1 transporter, which prevents intestinal uptake of dietary and biliary cholesterol and decreases cholesterol delivery to the liver, thus upregulating LDLR and increasing hepatic LDL-C uptake. Ezetimibe is affordable, well tolerated, and has outcomes benefits, as seen in the large Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) [60]. This trial found that, over a median six-year follow-up, patients with recent acute coronary syndrome (ACS) randomized to simvastatin plus ezetimibe versus simvastatin plus placebo had lower rates of the composite outcome of CV death, myocardial infarction, hospital admission for unstable angina, coronary revascularization 30 or more days after randomization, or stroke (HR: 0.94, 95% CI: 0.89–0.99), with similar adverse events [60]. An additional 20% LDL-C reduction can be expected by adding ezetimibe to statin therapy in FH patients [61, 62, 63].

Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase [64]. It lowers LDL-C through a mechanism similar to statins by interfering with intrahepatic cholesterol biosynthesis, resulting in the upregulation of LDLR on the hepatocyte surface. However, given that it is a prodrug activated only in the liver, the incidence of muscle-related adverse events is the same as seen in the placebo arm of several trials [65]. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony and CLEAR Wisdom phase 3 trials compared this drug to placebo in patients with ASCVD or HeFH on maximally tolerated statin therapy and found significant placebo-corrected LDL-C reductions of 18.1% and 17.4%, respectively, at 12 weeks [66, 67]. Adverse events were similar between the two groups, but higher rates of uric acid elevation were seen in the CLEAR Wisdom treatment group. Patients with HeFH made up a minority of the patients, with a pooled analysis showing greater placebo-controlled reductions of 22.3% in patients with HeFH (n = 112) as compared to 18.3% in patients without HeFH (n = 2897) [68]. This drug, along with a combination single-tablet bempedoic acid-ezetimibe, have been approved by the United States Food and Drug Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy in adults with HeFH or established ASCVD requiring additional LDL-C lowering. The CLEAR Outcomes trial recently compared bempedoic acid to placebo among patients with either established or at high risk for ASCVD and intolerant to statin therapy, demonstrating greater LDL-C reduction (21.1% reductions at six months in favor of bempedoic acid) and fewer major adverse CV events (HR: 0.87, 95% CI: 0.79–0.96) with bempedoic acid. This medication has not been assessed in patients with HoFH.

Lomitapide is an inhibitor of the microsomal triglyceride transfer protein, which plays an important role in lipoprotein synthesis in enterocytes and hepatocytes. Through the prevention of lipid transfer, lomitapide leads to reduced apoB-containing lipoprotein production in the small intestine (chylomicrons) and liver (VLDL-C) [69]. The LDLR-independent mechanism of lomitapide confers an advantage in patients with HoFH, hence its FDA approval for lipid-lowering in this population as an adjunct to a low-fat diet and other LLTs, including LDL apheresis. The efficacy and safety of lomitapide were studied in an open-label, phase 3, non-randomized, dose-escalating study of 29 patients above the age of 18 with HoFH [70]. The study demonstrated a potent LDL-C reduction of 50% at 26 weeks, 44% at 52 weeks, and 38% at 78 weeks. The adverse events were dose-dependent and included gastrointestinal symptoms, increased transaminase levels, and hepatic fat accumulation, with the drug carrying a boxed warning for risk of hepatotoxicity given the latter two events. The medication is both a substrate and inhibitor of cytochrome P450 3A4 with the potential for drug-drug interactions with other inhibitors of the enzyme, including statins and warfarin [69]. Finally, lomitapide is contraindicated in pregnancy since it may cause fetal harm. Given the above reasons, lomitapide prescribing in the United States is limited to physicians registered in a Risk Evaluation and Mitigation Strategy program. Lomitapide’s long-term efficacy and safety remain under investigation in the Lomitapide Observational Worldwide Evaluation Registry (LOWER) [71].

PCSK9 is primarily produced in the liver and is secreted as a low-abundance plasma protein. It binds LDLR on the surface of hepatocytes, leading to its lysosomal degradation and decreased quantity of LDLR on the hepatic surface. Treatments targeting PCSK9 include monoclonal antibodies (evolocumab and alirocumab) that bind PCSK9, promoting its degradation, or a small interfering ribonucleic acid molecule (inclisiran) that inhibits translation of PCSK9 mRNA, blocking its synthesis [72]. Both approaches to PCSK9 inhibition lead to greater LDLR recycling, thus increasing hepatic LDL-C uptake [20]. Generally, a further decrease in LDL-C of 50–60% can be expected with the addition of PCSK9-inhibiting monoclonal antibodies in patients with HeFH on conventional LLT [73, 74, 75, 76, 77, 78]. In patients significantly above LDL-C goal on statin monotherapy, PCSK9 inhibition may be initiated directly in lieu of trialing ezetimibe. The PCSK9 monoclonal antibodies are well tolerated across trials, with the most common adverse events being injection site reactions, mild cold or flu-like symptoms, nasopharyngitis, and myalgias [79].

Evinacumab is a fully human monoclonal antibody targeted against angiopoietin-like 3 (ANGPTL3), a circulating inhibitor of lipoprotein lipase and endothelial lipase. ANGPTL3 inhibition leads to the increased activity of these enzymes, which reduces apoB-containing lipoproteins by promoting VLDL and remnant clearance [85]. The Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia (ELIPSE HoFH) phase 3 trial compared evinacumab to placebo in patients with HoFH not achieving LDL-C goal despite multiple LLT (77% on statins, 75% ezetimibe, 77% PCSK9 inhibitors, 25% lomitapide, and 34% lipid apheresis) and found a 49% placebo-controlled LDL-C reduction at 24 weeks [86]. The rate of adverse events was similar between the groups. In addition, the efficacy was unaffected by mutation type, with 72% placebo-controlled LDL-C reductions in those with virtually absent LDLR activity (n = 10). Evinacumab has FDA approval for use as an adjunct to other LLTs in adult and pediatric patients with HoFH aged 12 years and older.

Lipoprotein apheresis is the physical removal of apoB-containing lipoproteins from circulation. It lowers LDL-C by 50 to 76% acutely and is performed weekly or biweekly according to the severity of hypercholesterolemia [87]. No study has demonstrated clear benefits in survival or angiographic outcomes with lipoprotein apheresis [88, 89], although some studies indicate acute improvements in coronary microvascular dysfunction [90]. Despite its FDA approval, inadequate access, the burden of therapy, known side effects, and the growth of novel medical LLTs have led to heterogeneity in expert recommendations for apheresis initiation. The National Lipid Associated Expert Panel on FH recommendations, published in 2011, indicates lipoprotein apheresis in the following patients with inadequate response to maximal LLT after six months: HoFH with LDL-C $\ge$300 mg/dL; HeFH with LDL-C $\ge$300 mg/dL and 0–1 risk factors; HeFH with LDL-C $\ge$200 mg/dL and $\ge$2 risk factors or Lp(a) $\ge$50 mg/dL; and HeFH with LDL-C $\ge$160 mg/dL and $\ge$2 very high-risk characteristics (established CAD, other CV diseases, or diabetes) [91].

Surgical options have been considered in patients with HoFH, particularly children, who fail to reach the LDL-C goal with maximally tolerated LLT and cannot receive regular lipoprotein apheresis. Liver transplantation has been used in patients with HoFH to provide functional hepatic LDLRs, therefore decreasing LDL-C and improving the efficacy of LLT. Early reports of pediatric patients with HoFH undergoing liver transplantation have shown impressive LDL-C reduction [92]. Similar limited data has shown LDL-C reductions after portacaval shunt [93] and partial ileal bypass [94], but their effect has been variable. Given the lack of long-term efficacy data, the higher risk of complications and side effects, and the rise in novel medical therapies, these options are infrequently utilized.