Getting Low in Familial Hypercholesterolemia by Integritas Communications

FACULTY Michael H. Davidson, MD, FACC, FACP, FNLA Professor of Medicine Director of the Lipid Clinic The University of Chicago, Pritzker School of Medicine Chicago, Illinois

Dr. Michael Davidson is a nationally recognized expert on statins, novel lipidlowering drugs, and the reduction of coronary artery disease risk through diet and exercise. He specializes in heart disease prevention, teaching patients to take a proactive approach to managing cardiac risk factors. He earned his medical degree from The Ohio State University College of Medicine in Columbus, and completed his residency in Internal Medicine and fellowship in Cardiology at Rush University Medical Center in Chicago. An active researcher, Dr. Davidson’s clinical research background encompasses both pharmaceutical and nutritional clinical trials. His extensive research on statins, novel lipid-lowering drugs, and nonpharmacologic risk factor reduction has established him as a key opinion leader in this area. A proli ic author and lecturer on lipid disorders, nutrition, and atherosclerosis, Dr. Davidson has coordinated more than 1000 clinical trials in areas of preventive cardiology. He has published more than 250 articles for leading medical journals and has written several books on lipidology.

Dr. Davidson has been named one of "The Best Doctors in America" by Best Doctors Inc. for the past 10 years and was named Father of the Year by the American Diabetes Association in 2010. He has served as the president of the National Lipid Association.

Lipidologist and Founder Mobile Health Team Neenah, Wisconsin

Dr. Ann Liebeskind is an expert in lipidology, the study of cholesterol. One of the irst diplomates of the American Board of Clinical Lipidology, she holds board certi ications in Internal Medicine and Pediatrics, and treats both adults and children with cholesterol problems. A Wisconsin native, Dr. Liebeskind graduated from the University of Wisconsin Medical School and completed her internship and residency in Internal Medicine and Pediatrics at the University of Kentucky Hospital. Dr. Liebeskind started the irst combined pediatric and adult lipids clinic in Northeast Wisconsin in 2006 while working for A inity Health System. During her time at A inity, she worked with colleagues at the Mayo Clinic to create A inity Health System's COURAGE program, which went on to be o ered by Network Health Plan. She also worked with doctors from across the Fox Valley to bring the irst LDL apheresis program to Northeast Wisconsin. (LDL apheresis is a process for lowering cholesterol in people with very severe genetic diseases.) Blending her expertise in cholesterol with her fascination with technology, Dr. Liebeskind created an innovative private practice in 2014, Mobile Health Team. Using both of these passions, she has also developed tools for children and families to foster healthy lifestyles, improve their cholesterol, and achieve healthier futures. In 2015, she published Adventures in Cholesterol, a 28-page graphic novel created to empower children and parents in managing their cholesterol. She is the founder of Homework for Health, an online teaching resource to help health care practitioners, educators, and families manage cholesterol.

Dr. Liebeskind is a faculty member of the National Lipids Association's Foundations in Lipidology course and an expert in familial hypercholesterolemia (FH). In 2014, Dr. Liebeskind was named a regional expert in pediatric obesity, serving as a designated Childhood Obesity Advisor for Continuing Health (COACH) for the American Academy of Pediatrics. In 2018, she was awarded the Midwest Lipid Association's Chapter President's Service Award at the National Lipid Association Scienti ic Session in Las Vegas, Nevada. A Fellow of the National Lipid Association and of the American Academy of Pediatrics, she chairs the website committee for the National Lipid Association and serves as a board member of the Foundation of

Ann Liebeskind, MD, FAAP, FNLA

the National Lipid Association. Dr. Liebeskind is an o icer of the Midwest Lipid Association Chapter and has spoken nationally for the American Academy of Pediatrics and the National Lipid Association on a variety of topics regarding lipid management and medical practice management.

PREAMBLE Target Audience The educational design of this activity addresses the needs of lipidologists, cardiologists, pediatricians, and specialist clinicians who manage patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels due to heterozygous or homozygous familial hypercholesterolemia (FH).

Statement of Need/Program Overview FH is marked by high levels of circulating LDL-C, leading to increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Patients frequently remain undiagnosed, resulting in poor outcomes and failure to diagnose family members. Clinicians should be aware of the diagnostic criteria as well as the importance of genetic testing. FH generally responds inadequately to traditional lipid-lowering therapies such as statins and often necessitates more e ective biologic therapies. A multidisciplinary approach is needed in treating FH, and clinicians should be aware of recent discoveries in lipid genetics, currently endorsed diagnostic criteria, and recently approved and emerging agents to treat FH.

Educational Objectives After completing this activity, the participant should be better able to: • Describe the pathophysiology and genetic underpinnings of FH • Diagnose FH based on clinical manifestations, genetic mutations, family screening results, and evaluation of medical records and claims data • Discuss the clinical pro iles and recent trial evidence for current targeted therapies for FH • Tailor lipid-lowering therapy and multidisciplinary care for patients with FH according to disease subtype, severity, comorbidities, and treatment history

In support of improving patient care, this activity has been planned and implemented by The National Lipid Association and Integritas. The National Lipid Association is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education

(ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the health care team.

Criteria for Success A statement of credit will be available upon completion of an online evaluation/ claimed credit form at the end of this activity. The deadline to claim credit is December 17, 2022. For assistance regarding credit, please contact cme@lipid.org.

Physician Credit Designation Statement NLA designates this Online Activity for a maximum of 1.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physician Assistants NCCPA accepts AMA PRA Category 1 Credits™ from organizations accredited by the ACCME.

Disclosure Statement It is the policy of NLA to ensure independence, balance, objectivity, scienti ic rigor, and integrity in all of its continuing education activities. The faculty must disclose to the participants any signi icant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identi ied con lict of interest is resolved by NLA prior to accreditation of the activity. NLA planners and reviewers have no relevant inancial relationships to disclose. The faculty have the following relevant inancial relationships with ineligible companies: Michael H. Davidson, MD, FACC, FACP, FNLA

Nothing to disclose

Ann Liebeskind, MD, FAAP, FNLA

Nothing to disclose

The NLA and Integritas planners and managers have no relevant inancial relationships with ineligible companies.

Disclosure of Unlabeled Use and Investigational Product This educational activity may include discussion of uses of agents that are investigational and/or unapproved by the US Food and Drug Administration. Please refer to the o icial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer This course is designed solely to provide the health care professional with information to assist in his/her practice and professional development and is not to be considered a diagnostic tool to replace professional advice or treatment. The course serves as a general guide to the health care professional, and therefore, cannot be considered as giving legal, nursing, medical, or other professional advice in speci ic cases. The NLA speci ically disclaims responsibility for any adverse consequences resulting directly or indirectly from information in the course, for undetected error, or through reader’s misunderstanding of content.

Permissions The National Lipid Association acknowledges that permissions have been obtained for use of all copyrighted materials, including graphs, tables, pictures, and charts printed in this activity syllabus. Permissions have also been obtained from identi iable patients in photographs and other images, consistent with the US Department of Health and Human Services (DHHS) Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations for individual privacy.

Instructions to Receive Credit In order to receive credit for this activity, the participant must complete the preactivity questionnaire, score 75% or better on the posttest, and complete the program evaluation.

Fee Information & Refund/Cancellation Policy

There is no fee for this educational activity.

INTRODUCTION Familial hypercholesterolemia (FH) is a congenital disorder of lipid metabolism marked by high levels of circulating low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD).1 While diagnosis of FH often can be made based on characteristic clinical signs, family history, and laboratory evaluations, genetic testing provides a de initive diagnosis by pinpointing speci ic underlying mutations.2,3 Such indings help determine the choice of treatment and, ideally, lead to further screening of the patient’s relatives to identify other potential cases. Aggressive lipid lowering, usually requiring a combination of drugs, is key to managing FH and reducing ASCVD risk. If patients do not reach LDL-C targets using standard therapies at optimal doses, new and emerging drugs with novel mechanisms, such as monoclonal antibodies, may be indicated.4,5 FH is a lifelong condition requiring clinicians to adopt a multidisciplinary approach that tailors therapy to the needs and preferences of patients and their families with the goal of reducing risk of cardiovascular events.3 This eHealth SourceTM discusses recent discoveries in lipid genetics, describes current diagnostic criteria, reviews clinical trial data on the safety and e icacy of cholesterol-lowering agents, and o ers practical management strategies to lower risk of ASCVD and optimize outcomes for patients with FH.

References 1. Brown EE, Sturm AC, Cuchel M, et al. Gene c tes ng in dyslipidemia: a scien Associa on. J Clin Lipidol. 2020;14(4):398-413.

c statement from the Na onal Lipid

2. Bianconi V, Banach M, Pirro M. Why pa ents with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med. 2021;31(4):205-215. 3. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult pa ents: clinical guidance from the Na onal Lipid Associa on Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 suppl):S1-S8. 4. Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal an bodies by iden fying pa ents most likely to bene t. A consensus statement from the Na onal Lipid Associa on. J Clin Lipidol. 2019;13(4):525-537.

5. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383(8):711-720.

CHAPTER 1

EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF FAMILIAL HYPERCHOLESTEROLEMIA Epidemiology of FH

Familial hypercholesterolemia (FH) is among the most common congenital disorders (Figure 1.1).1 There are 2 main subtypes: heterozygous FH (HeFH) results when the child inherits 1 or more mutations in lipid-regulating genes from 1 parent, while homozygous FH (HoFH) involves alleles inherited from both parents.

Estimates of prevalence vary, depending on the population studied and the diagnostic criteria applied, but in the United States, HeFH a ects between 1 in 250 to 300 adults, or about 1.1 to 1.3 million cases.6 HoFH is rare, with an estimated prevalence between 1 in 160,000 to 320,000 people, or more than 30 million cases worldwide.7,8 Rates are higher in certain populations, including French Canadians, Lebanese, and South Afrikaners.9 Importantly, despite the ubiquity of FH, more than 90% of cases remain undiagnosed.8,10

Genetic Causes of FH Most cases of FH are monogenic, arising from mutations in one of three key genes involved in lipid metabolism: LDLR, APOB, and PCSK9. The LDLR gene codes for low-density lipoprotein (LDL) receptors (LDLRs) on the membranes of liver cells. These receptors bind with LDL cholesterol (LDL-C) and remove it from circulation. There are more than 1000 known mutations in LDLR that can cause FH, through nonsense mutations, missense mutations, insertions, deletions, or rearrangements in DNA.8,11 These changes can lead to the reduction in the numbers (or complete absence) of these receptors, or they can cause any of several defects in LDL metabolism: impaired binding between LDL and LDLR, blocked transport of the LDL/LDLR complex into the Golgi apparatus, defective internalization of LDL/LDLR into the liver, or reduced recycling of LDL particles.12 Such defects result in abnormally high levels of LDL-C in circulation. Most (90% to 95%) cases of FH involve mutations in LDLR.11 Mutations can also appear in APOB, which codes for apolipoprotein B (ApoB), a protein present on the surface of LDL particles that serves as the ligand for LDLR.11,13 ApoB defects interfere with the ability of LDL-C to bind to receptors. Another 5% to 10% of FH cases arise from mutant APOB alleles, mostly among Northern Europeans; pathogenic APOB mutations are rare in other populations.13,14

PCSK9 codes for an enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to an extracellular part of the LDLR (a di erent site than that involving ApoB). The LDLR is internalized into hepatocytes and tra icked to a lysosome, where it is broken down or recycled back to the hepatocyte surface.15 PCSK9 prevents the LDLR from forming a closed loop, which makes LDLR more vulnerable to degradation. Thus, LDLRs that are not bound to PCSK9 are more easily recycled to the cell surface, where they can continue to remove LDL-C particles from circulation. Mutations in PCSK9 that increase the ability of the PCSK9 protein to promote LDLR degradation are known as “gain-of-function” mutations.8 Drugs classi ied as PCSK9 inhibitors act by blocking the activity of the enzyme, resulting

in increased numbers of LDLRs, thereby reducing circulating LDL-C particles. PCSK9 mutations account for less than 5% of FH cases.11,14 FH arising from mutations in LDLR, APOB, or PCSK9 is transmitted through autosomal dominant inheritance. A very rare form of FH has been identi ied involving autosomal VIDEO 1: LDL Metabolism in FH recessive mutations in the Michael H. Davidson, MD, FACC, FACP, FNLA LDLRAP1 gene, which codes for LDL receptor accessory protein 1, also involved in internalization of the LDLR and LDL-C ligand (Supplementary video 1).13 The severity of hypercholesterolemia and the risk for atherosclerotic cardiovascular disease (ASCVD) is directly related to the speci ic mutations involved and their e ects on LDLR. Receptor-defective variants reduce LDLR function by up to 75%.16 Variants that result in loss of all or virtually all (<2%) LDLR activity, the result of homozygous inheritance of 2 mutated alleles, are called receptor-negative (or receptor-null) mutations.17 Compared with individuals with receptor-defective mutations, those with receptor-negative HoFH have higher LDL-C levels, more accelerated disease, reduced response to conventional lipid-lowering therapy, and poorer outcomes.16

Individuals sometimes present with a clinical phenotype that resembles FH with high LDL-C, but genetic testing is unable to identify the single causative genetic mutation in either LDLR, APOB, or PCSK9. In these cases, the individual is likely to have inherited a greater-than-average number of single-nucleotide polymorphisms (SNPs) that cause mutations in the various alleles involved in LDL-C metabolism. Brandts and colleagues refer to this form of the disease as polygenic “familial hypercholesterolemia”; their use of quotation marks suggests that the polygenic form is not inherited according to the same mendelian patterns as monogenic FH.11 The authors posit that distinguishing between monogenic and polygenic FH may lead to more accurate screening, better risk evaluation, and more e ective treatment.

CVD Burden of FH The main concern arising from FH is the extremely high risk of cardiovascular disease. FH is the most common genetic cause of ASCVD, a broad term that encompasses acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease of atherosclerotic origin.8 The problem begins before birth, as the fetus is exposed to elevated levels of LDL-C in utero.18 High LDLC results in premature ASCVD arising in mid-adulthood (age 55-60 years) in individuals with HeFH, or in early adulthood or even childhood in individuals with HoFH.9

The risk of developing ASCVD is signi icantly higher among people with FH compared with the general population.10 Clearly, a high level of LDL-C is the main culprit underlying the accelerated progression of atherosclerosis.11 But variability in the way ASCVD manifests in patients with FH suggests that other genetic or environmental factors may also play a role.9 In one study, individuals who had LDLC levels ≥190 mg/dL but no FH genetic mutations had a 6-fold higher risk for coronary artery disease (CAD) compared with those with LDL-C <130 mg/dL, while among those with both LDL-C ≥190 mg/dL and an FH pathogenic mutation, the risk was 22 times higher.19 Other reports show the risk can be even higher (Figure 1.2).11 In a registry of patients with HeFH, 48% of whom were treated with 3-hydroxy-3methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins), the irst cardiovascular event occurred at a mean age of 47 years.20 More than one third of these patients had a recurrent event; 55% of those events occurred within 3 years of the initial event.20 Gender di erences may also be a factor. A recent retrospective study in the United Kingdom found that women with FH were likely to be prescribed statin therapy 5 years later than men and were likely to have higher rates of CVD morbidity.21

Mortality Burden of FH FH also increases the risk of premature death from ASCVD, despite appropriate treatment with statins. In a Norwegian registry, CVD was the cause of death in 50% of patients with FH.22 A UK registry study observed the excess mortality rate to be 2.4 times higher among patients with de inite FH compared with the general population.23 A 4-year follow-up study in Israel reported that 10% of 279 patients with FH had died at a mean age of 55 ± 8 years, compared with a mean age of death of 67 ± 6 years from noncardiovascular (or unknown) causes.24 Patients in this FH cohort were found to have substantial polyvascular involvement and had presented to the clinic at a young age.

Key Take-Home Messages • FH is a common congenital disorder • Mutations for both HeFH and HoFH are typically found in LDLR, but may also occur in APOB or PCSK9 • Mutations in LDLR, APOB, and PCSK9 all disrupt normal LDL-C metabolism, leading to extremely high cholesterol levels that are characteristic of FH

• Severity of hypercholesterolemia and risk for future ASCVD is linked to the speci ic mutation

• Patients with FH, particularly HoFH, have an increased risk for ASCVD, which often occurs prematurely • FH conveys a signi icant mortality burden due to premature ASCVD

References 1. Brown EE, Sturm AC, Cuchel M, et al. Gene c tes ng in dyslipidemia: a scien Associa on. J Clin Lipidol. 2020;14(4):398-413.

c statement from the Na onal Lipid

2. Johns Hopkins University. Online Mendelian Inheritance in Man. 2021; h ps://www.omim.org/. Accessed November 4, 2021. 3. Streetly A, La novic R, Henthorn J. Posi ve screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005-07. J Clin Pathol. 2010;63(7):626-629. 4. Orphanet. Prevalence and incidence of rare diseases: bibliographic data. 2021; h ps://www.orpha.net/orphacom/ cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabe cal_list.pdf. Accessed November 4, 2021. 5. Na onal Organiza on for Rare Disorders. The rare disease database. 2021; h ps://rarediseases.org/. Accessed November 4, 2021. 6. Peterson AL, McNeal CJ, Wilson DP. Preven on of atherosclero c cardiovascular disease in children with familial hypercholesterolemia. Curr Atheroscler Rep. 2021;23(10):64. 7. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modi ca on to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111-188. 8. Sturm AC, Knowles JW, Gidding SS, et al. Clinical gene c tes ng for familial hypercholesterolemia: JACC Scien Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680.

9. Bianconi V, Banach M, Pirro M. Why pa ents with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med. 2021;31(4):205-215. 10. Hu P, Dharmayat KI, Stevens CAT, et al. Prevalence of familial hypercholesterolemia among the general popula on and pa ents with atherosclero c cardiovascular disease: a systema c review and meta-analysis. Circula on. 2020;141(22):1742-1759. 11. Brandts J, Dharmayat KI, Ray KK, Vallejo-Vaz AJ. Familial hypercholesterolemia: is it me to separate monogenic from polygenic familial hypercholesterolemia? Curr Opin Lipidol. 2020;31(3):111-118. 12. My linaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS. Familial hypercholesterolemia: new horizons for diagnosis and e ec ve management. Front Pharmacol. 2018;9:707. 13. Singh S, Bi ner V. Familial hypercholesterolemia—epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. 14. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult pa ents: clinical guidance from the Na onal Lipid Associa on Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(suppl 3):S1-S8. 15. Page MM, Wa s GF. PCSK9 inhibitors—mechanisms of ac on. Aust Prescr. 2016;39(5):164-167. 16. Ito MK, Wa s GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs. 2015;75(15):1715-1724. 17. Blom DJ, Harada-Shiba M, Rubba P, et al. E cacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: the ODYSSEY HoFH trial. J Am Coll Cardiol. 2020;76(2):131-142.

ffi

18. Gidding SS, Champagne MA, de Ferran SD, et al. The agenda for familial hypercholesterolemia: a scien statement from the American Heart Associa on. Circula on. 2015;132(22):2167-2192.

19. Khera AV, Won HH, Peloso GM, et al. Diagnos c yield and clinical u lity of sequencing familial hypercholesterolemia genes in pa ents with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578-2589. 20. Béliard S, Boccara F, Cariou B, et al. High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: the French Familial Hypercholesterolemia Registry. Atherosclerosis. 2018;277:334-340. 21. Iyen B, Qureshi N, Weng S, et al. Sex di erences in cardiovascular morbidity associated with familial hypercholesterolaemia: a retrospec ve cohort study of the UK Simon Broome register linked to na onal hospital records. Atherosclerosis. 2020;315:131-137. 22. Krogh HW, Mundal L, Holven KB, Re erstøl K. Pa ents with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the me of death. Eur Heart J. 2016;37(17):1398-1405. 23. Humphries SE, Cooper JA, Seed M, et al. Coronary heart disease mortality in treated familial hypercholesterolaemia: update of the UK Simon Broome FH register. Atherosclerosis. 2018;274:41-46.

24. Shemesh E, Azaiza A, Zafrir B. Treatment gaps and mortality among pa ents with familial hypercholesterolemia and cardiovascular disease: a 4-year follow-up study. Eur J Prev Cardiol. 2020:2047487320932329.

CHAPTER 2

IDENTIFYING AND EVALUATING PATIENTS WITH FH Signs of FH The earlier familial hypercholesterolemia (FH) is diagnosed, the sooner medical management can begin. In the United States, diagnosis of FH is often made on the basis of clinical indings from the evaluation (patient and family history, physical examination, and laboratory tests).1 FH frequently goes unrecognized in its early stages; consequently—and unfortunately—a clinical diagnosis is sometimes made only after the patient experiences a premature atherosclerotic cardiovascular disease (ASCVD) event.2,3 Angina or myocardial infarction (MI) can occur in patients with FH as early as the third decade of life, and sudden death from MI has been reported in children with homozygous FH (HoFH) as young as 4 years.1 More typically, however, the median age of irst MI from FH is approximately 50 years in men and 60 years in women.1

Physical signs arising from sustained elevations of low-density lipoprotein cholesterol (LDL-C) are nonspeci ic for FH, but they may be present in a minority of cases and are more likely to develop as patients age.4 One characteristic sign that should trigger suspicion of FH is the appearance of xanthomas (raised subcutaneous fatty deposits) at any age, usually in Achilles and inger extensor tendons but sometimes arising in patellar and triceps tendons.4 Xanthomas are commonly missed on physical exam or are sometimes mistaken for warts (Figure 2.1A).5 Corneal arcus (white or gray arc-shaped lipid deposits around the cornea) may indicate FH when present in patients under age 40 to 45 years (Figure 2.1B). Xanthelasmas ( lat or slightly raised yellow growths on or near the eyelids) may be present as well (Figure 2.1C).6 Registry data on patients with FH suggest xanthomas, corneal arcus, and xanthelasmas occur in only about 10%, 30%, and 5% of cases, respectively.7

Diagnostic Criteria

Validated diagnostic criteria for FH include the Make Early Diagnosis to Prevent Early Death (MEDPED; US), the Dutch Lipid Clinic Network (DLCN; The Netherlands), and the Simon Broome Register Group (UK).1 Because MEDPED (Table 2.1) includes only age- and relative-speci ic cuto s for total cholesterol, it is less speci ic for FH.2 Dutch Lipid Clinic scoring (Table 2.2) distinguishes among de inite, probable, possible, and unlikely FH. Simon Broome is a somewhat simpler system, distinguishing only between de inite and possible diagnosis (Table 2.3).10 No consensus currently exists in the US concerning which diagnostic criteria should be used.

Con irming the presence of FH requires a careful di erential diagnosis that excludes other potential secondary causes of dyslipidemia, including hypothyroidism, nephrotic syndrome, obstructive liver disease, and diets high in saturated fat and cholesterol.1

Recommendations for Hypercholesterolemia Screening

Screening patients for hypercholesterolemia from early ages o ers an e ective, practical strategy for improving the timely and accurate diagnosis of FH. The universal screening strategy in the American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines on the Management of Blood Cholesterol acknowledges the importance of early diagnosis due to the potential onset of atherosclerosis at an early stage and distinguishes between children with and without inherited dyslipidemias. Initial lipid screening prior to sexual maturation (by age 9-11 years in the United States) facilitates diagnosis prior to the onset of lipid level changes associated with puberty.13 The American Association of Clinical Endocrinologists (AACE) endorses more targeted (selective) screening for children with high-risk conditions or a family history of hypercholesterolemia or premature ASCVD (Table 2.4).14 A third approach, known as cascade screening (discussed below), evaluates relatives of a patient who has been found to have FH.

The main purpose of screening is to determine levels of circulating LDL-C to establish the diagnosis and to serve as a baseline for determining therapeutic targets for LDL-C lowering (Table 2.5). Numerous published guidelines, including those from the AACE/American College of Endocrinology (ACE), AHA, and the National Lipid Association (NLA), state that the optimal LDL-C level is less than 100 mg/dL.13,15,16 Individuals with HeFH typically have LDL-C levels between 155 and 500 mg/dL, whereas people with HoFH can have LDL-C levels above 500 mg/dL.14

Genetic Testing in FH Genetic testing provides a de initive molecular diagnosis of FH in many (but not all) cases and can be o ered to any patient suspected of having the disease.2,7 Testing has many potential advantages. In addition to identifying mutations in any of the 3 key genes that cause FH, testing can screen for single-nucleotide polymorphisms (SNPs) found in polygenic patients and can distinguish between receptor-negative and receptor-defective variants.17,18 These indings can help clinicians stratify their patients’ risk and thus design more personalized treatment strategies, since, for example, certain variants predict higher cardiovascular disease risk and require more aggressive therapy.7,17 Because insurers often require prior authorization before allowing the use of approved novel therapies, genetic test results may have an impact on a patient’s eligibility for treatment coverage.18,19 Patients whose FH is con irmed through genetic testing are often motivated to initiate and adhere to their prescribed aggressive lipid-lowering strategy.17,18 Genetic evidence of an inherited dyslipidemia in an index patient (proband) can—indeed should—trigger cascade screening to identify other relatives who may have the condition.6,7

While genetic testing for FH is considered the gold standard, it is underused. Genetic testing is not widely available and, because it is not always covered by insurance, can be costly. However, the costs of next-generation DNA sequencing are dropping as the technology becomes more widespread.3,14,20 Clinicians should be aware of the wide variety in both risk scores and reporting, which may make it di icult to select a testing vendor. A clinical diagnosis by itself is often adequate for

identifying FH, and the treatment approach is usually the same regardless of whether genetic testing has been performed.21 Nevertheless, patient response to certain therapeutic classes can vary by LDL receptor mutations.

An advantage of genetic testing is to identify other individuals with FH who are at high risk of ASCVD and whose condition otherwise might not have been diagnosed.7 Pre- and post-genetic counseling should be o ered to patients (and their families) who have agreed to be tested to help them understand the basic facts of genetic inheritance, the potential misuse of test results (such as stigmatization or discrimination), the risk of ASCVD that FH poses to relatives of the person with a diagnosis, the treatment options available, and the importance of adhering to an aggressive lifelong lipid-lowering plan.1,6

Cascade Screening Because FH is inherited through an autosomal dominant pattern, cascade screening o ers an e icient, cost-e ective strategy for tracing relatives of an individual with FH to determine if they, too, are a ected.7,17 Based on systematic reviews of the evidence, the US Centers for Disease Control and Prevention (CDC), the UK National Institute for Health and Care Excellence, and the European Atherosclerosis Society have all endorsed cascade screening.7 ACC/AHA guidelines support reverse cascade screening of older relatives after a child is diagnosed with FH. Like cascade screening of children of adults diagnosed with FH, reverse cascade screening is e ective for identifying family members with FH and those at an increased risk for ASCVD.13 Cascade screening involves systematically conducting lipid pro iles and/or genetic testing in biological irst-degree relatives and, optimally, second- and even thirddegree relatives of an individual in whom FH has been probably or de initely diagnosed.18,22,23 The chance that a irst-degree relative of the index patient has FH is 50%, and the probability that a second-degree relative is a ected is 25%.5

Most cases of FH can be identi ied through cascade screening on the basis of LDLC (and, per some guidelines, total cholesterol) levels, but further genetic testing is recommended when the causative mutation is known.7,24 Assessing levels of lipoprotein(a) (Lp[a]) can further qualify ASCVD risk in those with FH.25

Current guidelines for managing FH call for conducting cascade screening in families, including children as young as 2 years of age.26 Ideally, clinicians should be prepared to assist patients in their e orts to reach out to their extended families, share the diagnosis, explain the associated risk, and recommend further assessment and treatment if needed (Supplementary video 2).18

VIDEO 2: Identifying Patients With FH Ann Liebeskind, MD, FAAP, FNLA

Key Take-Home Messages • Presence of premature MI, xanthomas, or corneal arcus should initiate an evaluation for a diagnosis of FH • A lipid panel—either fasting or nonfasting—can reveal LDL-C elevation that can help identify patients with FH • Diagnosis can be further con irmed by physical exam, family history, and genetic testing • Available guidelines di er on lipid cuto s for an FH diagnosis, but all provide recommendations based on both adults and children • Cascade screening is e ective at identifying family members with FH but it is rarely done

References 1. Gidding SS, Champagne MA, de Ferran SD, et al. The agenda for familial hypercholesterolemia: A scien statement from the American Heart Associa on. Circula on. 2015;132(22):2167-2192.

2. Bianconi V, Banach M, Pirro M. Why pa ents with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med. 2021;31(4):205-215.

3. Hu P, Dharmayat KI, Stevens CAT, et al. Prevalence of familial hypercholesterolemia among the general popula on and pa ents with atherosclero c cardiovascular disease: A systema c review and meta-analysis. Circula on. 2020;141(22):1742-1759.

4. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult pa ents: clinical guidance from the Na onal Lipid Associa on Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(suppl 3):S1-S8. 5. Singh S, Bi ner V. Familial hypercholesterolemia—epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. 6. Peterson AL, McNeal CJ, Wilson DP. Preven on of atherosclero c cardiovascular disease in children with familial hypercholesterolemia. Curr Atheroscler Rep. 2021;23(10):64. 7. Sturm AC, Knowles JW, Gidding SS, et al. Clinical gene c tes ng for familial hypercholesterolemia: JACC Scien Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680.

8. Katzmann J, Schürfeld C, März W, Laufs U. Case report-Rapid regression of xanthomas under lipoprotein apheresis in a boy with homozygous familial hypercholesterolemia. J Clin Lipidol. 2018;12(4):868-871. 9. Lock JH, Ross CA, Flaherty M. Corneal arcus as the presen ng sign of familial hypercholesterolemia in a young child. J AAPOS. 2018;22(6):467-468. 10. Humphries SE, Whi all RA, Hubbart CS, et al. Gene c causes of familial hypercholesterolaemia in pa ents in the UK: rela on to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006;43(12):943-949. 11. Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJP. Advanced method for the iden with inherited hypercholesterolemia. Semin Vasc Med. 2004;4(1):59-65.

ca on of pa ents

12. World Health Organiza on. Familial hypercholesterolaemia: report of a second WHO consulta on. Geneva, Switzerland;1998. 13. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Associa on Task Force on Clinical Prac ce Guidelines. Circula on. 2019;139(25):e1046-e1081. 14. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Associa on of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and preven on of cardiovascular disease. Endocr Pract. 2017;23(suppl 2):1-87. 15. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Associa on of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and preven on of cardiovascular disease algorithm—2020 Execu ve Summary. Endocr Pract. 2020;26(10):1196-1224. 16. Wilson PWF, Jacobson TA, Mar n SS, et al. Lipid measurements in the management of cardiovascular diseases: Prac cal recommenda ons a scien c statement from the na onal lipid associa on wri ng group. J Clin Lipidol. 2021. [Epub ahead of print] 17. Brandts J, Dharmayat KI, Ray KK, Vallejo-Vaz AJ. Familial hypercholesterolemia: is it me to separate monogenic from polygenic familial hypercholesterolemia? Curr Opin Lipidol. 2020;31(3):111-118. 18. Brown EE, Sturm AC, Cuchel M, et al. Gene c tes ng in dyslipidemia: a scien Associa on. J Clin Lipidol. 2020;14(4):398-413.

c statement from the Na onal Lipid

19. Kaufman TM, Warden BA, Minnier J, et al. Applica on of PCSK9 inhibitors in prac ce. Circ Res. 2019;124(1):32-37. 20. Ajufo E, deGoma EM, Raper A, Yu KD, Cuchel M, Rader DJ. A randomized controlled trial of gene c tes ng and cascade screening in familial hypercholesterolemia. Genet Med. 2021;23(9):1697-1704. 21. Ahmad ZS, Andersen RL, Andersen LH, et al. US physician prac ces for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry. J Clin Lipidol. 2016;10(5):1223-1229. 22. Lui DTW, Lee ACH, Tan KCB. Management of familial hypercholesterolemia: current status and future perspec ves. J Endocr Soc. 2021;5(1):bvaa122.

23. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general popula on: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490.

24. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modi ca on to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111-188. 25. Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical prac ce: a biomarker whose me has come. A scien c statement from the Na onal Lipid Associa on. J Clin Lipidol. 2019;13(3):374-392.

26. Peterson AL, Bang M, Block RC, Wong ND, Karalis DG. Cascade screening and treatment ini a on in young adults with heterozygous familial hypercholesterolemia. J Clin Med. 2021;10(14):3090.

CHAPTER 3

TARGETED THERAPIES FOR HOFH AND HEFH Setting Goals in LDL-C Reduction In patients with familial hypercholesterolemia (FH), aggressive use of lipid-lowering therapies beginning in childhood o ers hope for reducing the incidence of atherosclerotic cardiovascular disease (ASCVD) to rates comparable to those seen in individuals without FH.1 There is no known “ideal” low-density lipoprotein cholesterol (LDL-C) level.2 Generally, however, the goal is to reduce LDL-C levels to the greatest degree possible. Di erent guidelines promulgate somewhat di erent lipid targets. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend ≥50% reduction in LDL-C levels and stipulate that patients who still have LDL-C levels >100 mg/dL while on statins should escalate therapy to reduce their ASCVD risk.3 Beyond the percent reduction in LDL-C, most guidelines recommend LDL-C thresholds <100 mg/dL in adults with FH (either heterozygous FH [HeFH] or homozygous FH [HoFH]) without cardiovascular risk factors (eg, coronary heart disease or diabetes).4,5 For those with risk factors, the threshold is <70 mg/dL. European Society of Cardiology (ESC) and American Association of Clinical Endocrinologists (AACE) guidelines go further in suggesting a goal of <55 mg/dL in patients with a prior history of ASCVD.6,7 In children over 10 years of age, a reasonable target is <130 mg/dL, and in children aged 8 to 10 years at very high CVD risk the target is at least a 50% reduction.4,5,8,9 Di erent medications o er di erent intensities of LDL-C lowering and should be tailored to each patient’s needs. Combination therapy results in greater decrease in LDL-C levels.7 There is no current limit to how far LDL-C levels can safely be lowered. Several large trials involving LDL-C reductions to <50 mg/dL, or even <25 mg/dL, report no increase in signi icant adverse e ects, including cancer or hemorrhagic stroke.10

Conventional Lipid-Lowering Therapies

While lifestyle strategies are recommended, they are usually insu icient to achieve lipid goals. Statins are the mainstay of initial treatment for FH in children and

adults.3 These drugs work by inhibiting cholesterol synthesis in the liver. All statins are approved for use in children with HeFH by age 10 years; pitavastatin, pravastatin, and rosuvastatin can be prescribed in children with HeFH at age 8 years; rosuvastatin is indicated for children with HoFH as young as age 7 years.3,11 In Europe, statin treatment can be considered in children with HeFH as young as 6 years.7

“[B]oth ‘the lower, the better’ and ‘the younger, the better’ emerge as important concepts in pediatric HeFH management.”11 Statins can lower LDL-C up to 60%, though in patients with HoFH, high doses of statins typically achieve mean LDL-C reductions of 10% to 25%.12-14 Adding the cholesterol absorption inhibitor ezetimibe (in patients older than 10 years of age) can lower LDL-C by an additional 20%. Bile acid sequestrants can also be added to a regimen of statins and ezetimibe to achieve incremental reductions in LDL-C. However, these agents have generally low e icacy; they often can increase triglyceride levels, and many patients are unable to tolerate their gastrointestinal side e ects.15 Though no longer frequently used, extracorporeal LDL removal (apheresis) is an option for patients whose LDL-C levels remain high despite 6 months of maximally tolerated drug therapy or who have ongoing symptomatic ASCVD or associated high-risk factors.3,16 This option can be particularly useful in patients with certain genetic mutations, such as those with defects in APOB.17 Apheresis can reduce LDLC levels by up to 70% in a single session, and over the long term may promote regression of xanthomas and slow the progression of atherosclerosis. Typically, however, LDL-C levels rebound by up to 90% within 2 weeks after treatment. Apheresis requires referral to a lipid specialist, is time-consuming, and may not be available to many patients.18

As e ective as these conventional therapies can be, however, even in combination they often fail to reach the stringent targets that patients with FH need to minimize their risk of ASCVD. In recent years, several new agents with signi icantly greater e icacy have become available and changed the landscape of FH treatment.

Biologic Therapies for FH PCSK9 Inhibitors Drugs known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors block the activity of a protein that degrades LDL receptors, thereby increasing LDL receptor density and the rate at which LDL-C is removed from circulation.18,19 Results of clinical trials show that PCSK9 inhibitors, when combined with statin/ ezetimibe therapy at maximally tolerated doses, are safe and e ective and can reduce LDL-C by more than 60% in individuals with HeFH and 30% in those with HoFH.15,20 It is important to remember, however, that patients who are LDL receptor-negative will not bene it from PCSK9 inhibitors and e icacy will be reduced in patients with 1 receptor-negative gene and 1 receptor-defective gene.13

Alirocumab Alirocumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody. In the 78-week ODYSSEY FH I and FH II randomized studies, patients with HeFH whose LDL-C levels were inadequately controlled with maximally tolerated statins with or without other lipid-lowering therapies experienced mean reductions in LDL-C of 68 to 73 mg/dL by week 24 (Figure 3.1).21 About 3.5% of patients discontinued alirocumab therapy owing to adverse e ects, compared with 1.2% to 6.1% of patients in the placebo groups.

The phase 2 dose- inding ODYSSEY KIDS trial, involving 42 patients (age range, 8 to 17 years) with HeFH and baseline LDL-C levels of 160-189 mg/dL despite optimal lipid-lowering therapy, showed the greatest reductions in LDL-C (45%-46%) in the

groups taking higher doses based on body weight either every 2 or 4 weeks.22 The drug was well tolerated. In the ODYSSEY HoFH trial in adults with HoFH, treatment with alirocumab resulted in signi icantly and clinically meaningful reductions in LDL-C from baseline at 12 weeks (-27% vs +9% for placebo).23 Patients also experienced reductions in other lipid parameters (apolipoprotein B [ApoB], 30%; non–high-density lipoprotein cholesterol [HDL-C], 33%; total cholesterol, 27%; Lp[a], 28%; all least mean squares di erence vs placebo). The safety pro ile was similar to that of placebo. Alirocumab, originally approved by the United States Food and Drug Administration (FDA) in July 2015, is indicated as adjunctive therapy for adults with HeFH or HoFH.24 It is administered subcutaneously either every 2 or 4 weeks (typically every 2 weeks). Ongoing trials are evaluating the potential use of alirocumab in children.

Evolocumab The second PCSK9 inhibitor to reach the United States market is the fully human monoclonal antibody evolocumab. The randomized RUTHERFORD-2 trial in adults with HeFH showed signi icant reductions in mean LDL-C compared with placebo (Figure 3.2).25

A long-term randomized follow-up study in patients with HeFH receiving standardof-care treatment with or without evolocumab showed that mean LDL-C reductions of 54% were sustained through 48 weeks in the evolocumab group.26 The HAUSERRCT trial recruited young patients with HeFH (aged 10-17 years). The mean reduction in LDL-C was 44.5% in the evolocumab group compared with 6.2% in the

placebo group at week 24.27 Drug treatment also resulted in reductions in various lipid parameters from baseline (ApoB, 35%; non‒HDL-C, 41%; ratio of total cholesterol to HDL-C, 35%; Lp[a], 7%). An open-label, long-term study evaluating the e icacy of evolocumab in patients with FH aged ≥12 years reported mean reductions in LDL-C from baseline of 55% in HeFH and 21% in HoFH; these results were maintained over the 4 years of the study.28 A subset analysis of the open-label TAUSSIG study in patients with HoFH aged ≥12 years reported that drug treatment reduced LDL-C by 21%, whether the patient had undergone apheresis or not.29 Lp(a) decreased by 12% and HDL-C increased by 8% at week 48. Furthermore, the TESLA Part B study in HoFH showed that evolocumab reduced ultracentrifugation LDL-C by 31% compared with placebo.13 Evolocumab was irst approved by the FDA in August 2015 and is now indicated as adjunctive therapy for adults and children aged 10 years or older with HeFH or HoFH. It is administered subcutaneously either every 2 or 4 weeks in patients with HeFH and every 4 weeks in patients with HoFH, though patients may switch to every 2 weeks if there is an inadequate response.30

Inclisiran Inclisiran is also classi ied as a PCSK9-inhibiting agent, but it has a di erent mechanism of action from the monoclonal antibodies. This synthetic small interfering RNA targets the messenger RNA (mRNA) precursor for PCSK9 and thus disrupts the translation of the mRNA that encodes the PCSK9 protein.9 In the ORION-9 trial in adults with HeFH, inclisiran reduced LDL-C by 40%, compared with an increase of 8% seen in the placebo group.31 To date, there are no published cardiovascular outcomes trials for inclisiran, unlike alirocumab and evolocumab.

Inclisiran is available in Europe as a twice-yearly injection for adults with HeFH. As of this writing (November 2021), its approval in the United States has been held up by concerns about the manufacturing process. Ongoing trials are evaluating the potential use of inclisiran in adolescents with HeFH or HoFH and adults with HoFH. Inclisiran is administered every 3 months as a starting regimen then every 6 months as maintenance therapy.31

Drugs With Novel Mechanisms Microsomal triglyceride transfer protein (MTP) inhibitors (Lomitapide) Lomitapide, an oral agent approved for HoFH in 2012, acts by blocking an enzyme involved in transferring triglyceride onto ApoB during the process of assembling and secreting lipoproteins in the liver and intestine.9 This results in lower LDL-C levels regardless of the patient’s LDL receptor function. As an adjunct to other therapies, lomitapide lowered LDL-C by up to 50% with sustained e icacy over 5 years, signi icantly reducing the risk for irst cardiovascular events.32-35 Because lomitapide poses signi icant risk of adverse events, including transaminase elevations and hepatic steatosis, the drug is only available under a risk evaluation and mitigation strategy (REMS).9

Bempedoic Acid Bempedoic acid is a small molecule that is administered orally as a prodrug and, when activated, inhibits adenosine triphosphate citrate lyase (ACL), a key liver enzyme involved in cholesterol biosynthesis.9 A 12-week phase 3 trial in patients at high risk for CVD, including some with HeFH, on statin therapy found that bempedoic acid alone reduced LDL-C levels by 19% compared with placebo, and that the combination of bempedoic acid and ezetimibe resulted in synergistic LDLC lowering of 38% compared with placebo.36 Similarly, in the CLEAR Wisdom and CLEAR Harmony trials, patients with HeFH, established CVD, or both who were treated with bempedoic acid alone had LDL-C reductions that were 17% to 18% greater compared with placebo.37 Bempedoic acid was approved in 2020 alone and in combination with ezetimibe as an adjunctive LDL-lowering therapy for adults with HeFH or established ASCVD.38

ANGPTL3 Inhibitors (Evinacumab) Angiopoietin-like protein 3 (ANGPTL3) is a liver protein that acts by inhibiting 2 enzymes—lipoprotein lipase, which hydrolyzes triglycerides in very low-density lipoproteins (VLDL), and endothelial lipase, which hydrolyzes phospholipids in HDL. The net e ect is that ANGPTL3 reduces clearance of VLDL and HDL.9,39

Evinacumab, a human IgG4 monoclonal antibody, binds with ANGPTL3 and inhibits its activity. The randomized ECLIPSE HoFH trial found that evinacumab reduced mean LDL-C by 47% (135 mg/dL) from baseline in patients with HoFH aged 12 years or more (Figure 3.3).39 Even patients who carry the null variant (ie, who have

virtually no LDL receptors) responded to treatment, showing a 43% reduction in LDL-C, which compares with the 49% response seen in those with non-null variants. Adverse events were similar in the treatment and the placebo groups.

Evinacumab was approved by the FDA in February 2021 as adjunctive therapy for adults and children aged 12 years or older with HoFH.40 Ongoing trials are exploring the potential use of evinacumab in children as young as 5 years and are evaluating the long-term safety and e icacy of the drug.

The Therapeutic Horizon The search continues for therapies that o er greater e icacy and better safety for patients with HeFH and HoFH. In clinical trials, gemcabene, an oral small molecule, achieved dose-dependent LDL-C reductions of up to 39% in patients with HeFH and up to 11% in patients with HoFH.9 These results led the FDA to grant gemcabene orphan drug status for HoFH. Agents that target other speci ic proteins (such as ANGPTL4 or ANGPTL8) may be shown to provide better lipid control with fewer adverse e ects. Several trials are underway to evaluate treatment with a novel PCSK9 inhibitor, lerodalcibep. As research continues, we expect to see numerous early-stage therapies advance in trials.

Key Take-Home Messages

• The goal with pharmacologic treatment is to reduce LDL-C levels to the greatest extent possible, with lower targets among patients with more severe risk factors

• Statins are the mainstay of FH treatment though, even in combination with ezetimibe, they often fail to achieve satisfactory LDL-C levels • Patients who are LDL receptor-defective (rather than negative) can bene it from PCSK9 inhibitors on top of statins and ezetimibe

VIDEO 3: Shared Decision Making in FH

• Evinacumab targets ANGPTL3 and is e icacious in reducing LDL-C in patients with HoFH even if they carry the null variant.

Ann Liebeskind, MD, FAAP, FNLA

References 1. Sturm AC, Knowles JW, Gidding SS, et al. Clinical gene c tes ng for familial hypercholesterolemia: JACC Scien Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680.

2. Banerjee A, Alothman L, Couture P, et al. The lifelong burden of homozygous familial hypercholesterolemia. Can J Cardiol. 2019;35(10):1419.e1-1419.e4. 3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: execu ve summary: a report of the American College of Cardiology/American Heart Associa on Task Force on Clinical Prac ce Guidelines. Circula on. 2019;139(25): e1046-e1081. 4. Bianconi V, Banach M, Pirro M. Why pa ents with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med. 2021;31(4):205-215. 5. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: guidelines and new therapies. Atherosclerosis. 2018;277:483-492. 6. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Associa on of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and preven on of cardiovascular disease algorithm—2020 Execu ve Summary. Endocr Pract. 2020;26(10):1196-1224. 7. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modi ca on to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111-188. 8. My linaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS. Familial hypercholesterolemia: new horizons for diagnosis and e ec ve management. Front Pharmacol. 2018;9:707. 9. Lui DTW, Lee ACH, Tan KCB. Management of familial hypercholesterolemia: current status and future perspec ves. J Endocr Soc. 2021;5(1):bvaa122.

10. Faselis C, Imprialos K, Grassos H, Pi aras A, Kallistratos M, Manolis A. Is very low LDL-C harmful? Curr Pharm Des. 2018;24(31):3658-3664.

11. Peterson AL, McNeal CJ, Wilson DP. Preven on of atherosclero c cardiovascular disease in children with familial hypercholesterolemia. Curr Atheroscler Rep. 2021;23(10):64. 12. Gidding SS, Champagne MA, de Ferran SD, et al. The agenda for familial hypercholesterolemia: a scien statement from the American Heart Associa on. Circula on. 2015;132(22):2167-2192.

13. Raal FJ, Honarpour N, Blom DJ, et al. Inhibi on of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350. 14. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by sta n drugs. Am J Cardiol. 1997;80(1):106-107. 15. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Associa on of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and preven on of cardiovascular disease. Endocr Pract. 2017;23(suppl 2):1-87. 16. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult pa ents: clinical guidance from the Na onal Lipid Associa on Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(suppl 3):S1-S8. 17. Holyoak MD, Gorby LK, Moriarty PM. PCSK9 inhibitors, an ine ectual treatment for apolipoprotein B-100 defec ve familial hypercholesterolemia. Circula on. 2019;140(suppl 1):Abstract 16277. 18. Ito MK, Wa s GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs. 2015;75(15):1715-1724. 19. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of non-sta n therapies for LDL-cholesterol lowering in the management of atherosclero c cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(14):1785-1822. 20. Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal an bodies by iden fying pa ents most likely to bene t. A consensus statement from the Na onal Lipid Associa on. J Clin Lipidol. 2019;13(4):525-537. 21. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 pa ents with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003. 22. Daniels S, Caprio S, Chaudhari U, et al. PCSK9 inhibi on with alirocumab in pediatric pa ents with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study. J Clin Lipidol. 2020;14(3):322-330.e325. 23. Blom DJ, Harada-Shiba M, Rubba P, et al. E cacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: the ODYSSEY HoFH trial. J Am Coll Cardiol. 2020;76(2):131-142. 24. US FDA. Praulent (alirocumab) prescribing informa on. 2021; h ps://www.regeneron.com/downloads/ praluent_pi.pdf. Accessed November 8, 2021. 25. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibi on with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340. 26. Hovingh GK, Raal FJ, Dent R, et al. Long-term safety, tolerability, and e cacy of evolocumab in pa ents with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017;11(6):1448-1457. 27. Santos RD, Ruzza A, Hovingh GK, et al. Evolocumab in pediatric heterozygous familial hypercholesterolemia. N Engl J Med. 2020;383(14):1317-1327. 28. Santos RD, Stein EA, Hovingh GK, et al. Long-term evolocumab in pa ents with familial hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565-574. 29. Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conven onal drug therapy, with or without apheresis, in pa ents with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017;5(4):280-290.

ffi

30. US FDA. Repatha (evolocumab) prescribing informa on. 2021; h ps://www.pi.amgen.com/~/media/amgen/ repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf. Accessed November 8, 2021.

31. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. 32. Cuchel M, Meagher EA, du Toit Theron H, et al. E cacy and safety of a microsomal triglyceride transfer protein inhibitor in pa ents with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-46. 33. Harada-Shiba M, Ikewaki K, Nohara A, et al. E cacy and safety of lomitapide in Japanese pa ents with homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2017;24(4):402-411. 34. Blom DJ, Averna MR, Meagher EA, et al. Long-term e cacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in pa ents with homozygous familial hypercholesterolemia. Circula on. 2017;136(3):332-335. 35. Nohara A, Otsubo Y, Yanagi K, et al. Safety and e cacy of lomitapide in Japanese pa ents with homozygous familial hypercholesterolemia (HoFH): results from the AEGR-733-301 long-term extension study. J Atheroscler Thromb. 2019;26(4):368-377. 36. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus eze mibe xed-dose combina on in pa ents with hypercholesterolemia and high CVD risk treated with maximally tolerated sta n therapy. Eur J Prev Cardiol. 2020;27(6):593-603. 37. Polychronopoulos G, Tziomalos K. Treatment of heterozygous familial hypercholesterolemia: what does the future hold? Expert Rev Clin Pharmacol. 2020;13(11):1229-1234. 38. US FDA. Nexletol (bempedoic acid) prescribing informa on. 2020; h ps://www.accessdata.fda.gov/drugsa da_docs/ label/2020/211616s000lbl.pdf. Accessed November 8, 2021. 39. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383(8):711-720.

ffi

40. US FDA. Evkeeza (evinacumab) prescribing informa on. 2021; h ps://www.regeneron.com/downloads/ evkeeza_pi.pdf. Accessed November 8, 2021.

CHAPTER 4

DEVELOPING LIPID-LOWERING MANAGEMENT PLANS FOR FH Screening, Diagnosis, and Risk Assessment Before e ective therapies became available, most patients with familial hypercholesterolemia (FH) developed premature atherosclerotic cardiovascular disease (ASCVD); typically, those whose homozygous FH (HoFH) went untreated rarely survived much beyond the age of 30 years.1 Today the picture is much brighter. A comprehensive, multidisciplinary management strategy focused on reducing cardiovascular risk and tailored to address the needs of individual patients and their caregivers can improve the quality, as well as the quantity, of life for people with FH. Timely and accurate diagnosis of FH is the irst step. As discussed earlier, screening can identify individuals with, or at risk for, FH. This can be accomplished through universal, selective, or cascade screening. A diagnosis of FH is established with 2 low-density lipoprotein cholesterol (LDL-C) levels, obtained at least 3 months apart, that are ≥190 mg/dL (adults) or ≥160 mg/dL (children) if there is a family history of severely elevated cholesterol, premature ASCVD, or positive genetic testing for an LDL-C–raising gene defect.2,3

Calculating ASCVD risk is key to determining treatment goals and strategies (Figure 4.1).

Standard cardiovascular risk assessment tools, such as the Framingham Risk Score or the American College of Cardiology’s ASCVD Risk Estimator Plus, are not appropriate or accurate for use in individuals with FH because of the numerous risk factors in FH outside of traditional risk factors.5,6 Other validated tools are available, however. For example, the SAFEHEART risk equation calculates ASCVD risk based on 8 variables (age, sex, history of CVD, blood pressure, body mass index, smoking, LDL-C levels, and Lp[a] levels). A study in a registry cohort of 2404 adults with FH from Spain found SAFEHEART to be a simple and accurate tool for assessing 5-year ASCVD risk, at least in this relatively homogeneous European population.7 Regardless of risk status, treatment with high-potency statins should begin as soon as a clinical diagnosis of HoFH is made.5

Lp(a) is a plasma lipoprotein made up of an LDL-like particle linked to Apo(a).8 A level of Lp(a) ≥50 mg/dL is an important independent marker for increased early ASCVD risk, even among patients already at very high risk. Lp(a) levels tend to be

higher in HoFH than in heterozygous FH (HeFH), and knowing the patient’s Lp(a) level can help guide therapeutic decisions.9-12 One study found that children with FH and a family history of early-onset ASCVD were 3 times more likely to have Lp(a) ≥50 mg/dL compared with those from families with late-onset ASCVD.13 In fact, family history of early ASCVD can be a better predictor of a child’s Lp(a) level than peak LDL-C levels.13 Although no drugs are available that speci ically reduce Lp(a), lower levels of Lp(a) have been achieved in patients with FH treated with aggressive LDL-C‒lowering drugs, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.14 Genetic testing is invaluable for ASCVD risk assessment in FH. Most cases of FH arise from mutations in LDLR; patients with the less-common APOB and PCSK9 mutations appear to be at lower risk.6 Mutations a ecting innate immunity or cell motility can decrease risk, whereas risk rises with mutations a ecting lipoprotein metabolism, oxidative stress, the in lammatory response, the renin angiotensin aldosterone system (RAAS), coagulation, or the expression of red blood cell antigens.4

The presence and extent of vascular injury can stratify patients’ risk still further. Coronary artery calcium (CAC) is a robust surrogate marker of atherosclerotic burden that predicts coronary events in asymptomatic middle-aged patients with FH.15 Use of coronary computed tomography angiography (CTA) distinguishes between noncalci ied and calci ied plaques of su icient size.9 CAC scores can help clinicians reclassify patients from high to very high risk, which has implications on the choice of therapy. However, CAC can have a heterogeneous presentation; a recent meta-analysis found that approximately 45% of patients with molecularly de ined FH (mean age 47 years) did not have evidence of CAC.16 The Montreal FH Score (MFHS) uses 5 variables (age, sex, hypertension, high-density lipoprotein cholesterol [HDL-C] levels, and smoking) to stratify ASCVD risk in patients with FH. A multivariate analysis in patients with FH and only LDLR mutations found that MFHS was the only factor that remained signi icant in predicting whether a patient has a CAC score greater than zero (Figure 4.2).17

For patients with HeFH on standard therapy (statin with or without ezetimibe) who have CAC scores above zero, clinicians should consider adding a PCSK9 inhibitor (monoclonal antibody or small interfering RNA drug) or angiopoietin-like protein 3 (ANGPTL3) inhibitor to the regimen.18 Other imaging modalities may also play a role in risk evaluation. Ultrasound can assess carotid intima-media thickness (cIMT), which is typically greater in children with FH by age 8 or 10 years compared with their siblings without FH.9 Positron emission tomography (PET) can document arterial wall in lammation. Magnetic resonance imaging (MRI) detects aortic lesions.9 While routine imaging is not recommended for children with HeFH, it is frequently necessary for managing children with HoFH.4,8

Setting—and Achieving—Treatment Goals

Aggressive LDL-C lowering is the goal of treatment for all patients with FH. The target is to reduce LDL-C by at least 50% from baseline. Ideally therapy should aim to achieve goals of <100 mg/dL in FH and <70 mg/dL for adult patients with ASCVD or another risk factor, such as diabetes. Current European guidelines and the American Association of Clinical Endocrinology (AACE) tend to call for even more stringent LDL-C targets of <55 mg/dL in individuals with major risk factors.14,19 For pediatric patients, the goal is <130 mg/dL, but there appears to be no risk if lower levels are achieved. The risk strati ication tools and methodologies described above

should help clinicians determine which of their patients should be treated more aggressively. The choice of therapy is often driven by several factors beyond safety and e icacy. Access to certain drugs may be limited by insurers. Clinicians must often obtain prior authorization before VIDEO 4: Patient Education and prescribing newer Improving Adherence medications, a process that Michael H. Davidson, MD, FACC, FACP, FNLA can be time-consuming, burdensome, and frustrating.20,21 Some risk-averse patients may refuse to use newly approved agents that lack long-term data. Clinicians should anticipate potential barriers to selecting and implementing therapy. For example, they should consider developing a protocol to document the factors supporting their decisions to prescribe a PCSK9 inhibitor or an ANGPTL3 inhibitor, including family history; results of physical examination, laboratory evaluations, and genetic testing; FH diagnostic criteria scores; and results of imaging or other pertinent testing, such as Lp(a) levels.20 The likelihood that patients will adhere to their prescribed regimen increases when their values, beliefs, and preferences are taken into account when making therapeutic choices.22 This approach, known as shared decision making (SDM), involves focused discussions with clinicians that help patients weigh the risks and bene its of available options and choose a treatment strategy that best meets their needs.23 Clinicians can facilitate the SDM process by being prepared to provide factual information, discussing all pertinent treatment options in a balanced manner, and being sensitive to the psychosocial burden on patients and their families of having to manage a lifelong, potentially fatal illness (Supplementary video 4).

The FH Care Team

E ective management of patients with FH requires a comprehensive approach at all levels of health care. As gatekeepers to the health care system, primary care clinicians play a vital role because they are chie ly responsible for screening

patients and diagnosing FH.2,5 These providers also are well positioned to educate patients about the disease, the risks and bene its of treatment, strategies for managing adverse e ects, and techniques for coping with anxiety and improving adherence to the treatment regimen.9 Lipid specialists (cardiologists, endocrinologists, or others with specialized lipid training) are crucial members of the care team.2 Management of all patients with HoFH, and of children with FH, should be handled by a specialist.24 Referral to a specialist is appropriate for patients who have high baseline LDL-C levels, are at high risk for ASCVD and are intolerant to statins or other FH medications, or who do not achieve lipid targets with irst- and second-line medications. Referral is also strongly recommended for special populations, including children, adolescents, and women during pregnancy.21 A registered dietitian nutritionist can provide invaluable guidance to patients and families about the importance of healthy eating.2,21 Genetic counseling should be o ered both before and after the patient submits to genetic testing.25 Patients need to understand the basic facts of inherited disease and should be informed about the bene its, limitations, potential risks, costs, and social implications of testing.9 A genetic counselor can interpret the results of the test and explain them in lay terms. The counselor can also emphasize the importance of cascade screening to identify other family members potentially at risk for FH.

Call to Action: Establish a multidisciplinary care team consisting of a primary care provider, lipid specialist, dietitian, and genetic counselor.

Key Take-Home Messages • There are speci ic scoring systems to calculate risk of ASCVD in patients diagnosed with FH • Imaging such as MRI or CTA can further stratify patients • Accessibility of PCSK9 inhibitors or ANGPTL3 inhibitors can be dictated by insurance companies

• SDM will increase adherence

• A care team should include a primary care provider; specialists, particularly for children, those with HoFH, and pregnant patients; a dietitian; and genetic counselors

Conclusion FH is an inherited condition that carries a signi icant risk of premature ASCVD. Advances in genetics have led to the discovery of numerous underlying mutations and variants that interfere with lipid metabolism and result in pathologically elevated levels of LDL-C. Screening can identify patients who have, or who are at risk for, FH. Statins (with or without ezetimibe) are the irst line of treatment but are often insu icient in themselves to achieve aggressively low LDL-C targets. Newer agents, including the PCSK9 inhibitors and drugs with other novel mechanisms, are available as adjunctive therapies that help patients reach their lipid targets and reduce the risk of cardiovascular events. E ective, comprehensive management of FH requires a multidisciplinary approach incorporating drug therapy, lifestyle guidance, and supportive counseling.

References 1. Banerjee A, Alothman L, Couture P, et al. The lifelong burden of homozygous familial hypercholesterolemia. Can J Cardiol. 2019;35(10):1419.e1-1419.e4. 2. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult pa ents: clinical guidance from the Na onal Lipid Associa on Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(suppl 3):S1-S8. 3. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Associa on of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and preven on of cardiovascular disease. Endocr Pract. 2017;23(suppl 2):1-87. 4. Bianconi V, Banach M, Pirro M. Why pa ents with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med. 2021;31(4):205-215. 5. Hemphill L, Goldberg A, Hovingh K, Cohen J, Karalis DG. Recogni on and treatment of homozygous familial hypercholesterolemia by primary care physicians: a survey from the Na onal Lipid Associa on. J Gen Intern Med. 2020;35(7):2225-2227. 6. Sarraju A, Knowles JW. Gene c tes ng and risk scores: impact on familial hypercholesterolemia. Front Cardiovasc Med. 2019;6:5. 7. Pérez de Isla L, Alonso R, Mata N, et al. Predic ng cardiovascular events in familial hypercholesterolemia: the SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study). Circula on. 2017;135(22):2133-2144. 8. Peterson AL, McNeal CJ, Wilson DP. Preven on of atherosclero c cardiovascular disease in children with familial hypercholesterolemia. Curr Atheroscler Rep. 2021;23(10):64. 9. Gidding SS, Champagne MA, de Ferran SD, et al. The agenda for familial hypercholesterolemia: A scien statement from the American Heart Associa on. Circula on. 2015;132(22):2167-2192.

10. Raal FJ, Honarpour N, Blom DJ, et al. Inhibi on of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350.

11. Singh S, Bi ner V. Familial hypercholesterolemia—epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. 12. Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical prac ce: A biomarker whose me has come. A scien c statement from the Na onal Lipid Associa on. J Clin Lipidol. 2019;13(3):374-392. 13. Zawacki AW, Dodge A, Woo KM, Ralphe JC, Peterson AL. In pediatric familial hypercholesterolemia, lipoprotein(a) is more predic ve than LDL-C for early onset of cardiovascular disease in family members. J Clin Lipidol. 2018;12(6):1445-1451. 14. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Associa on of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and preven on of cardiovascular disease algorithm—2020 Execu ve Summary. Endocr Pract. 2020;26(10):1196-1224. 15. Alonso R, Perez de Isla L, Muñiz-Grijalvo O, Mata P. Barriers to early diagnosis and treatment of familial hypercholesterolemia: current perspec ves on improving pa ent care. Vasc Health Risk Manag. 2020;16:11-25. 16. Mszar R, Grandhi GR, Valero-Elizondo J, et al. Absence of coronary artery calci ca on in middle-aged familial hypercholesterolemia pa ents without atherosclero c cardiovascular disease. JACC Cardiovasc Imaging. 2020;13(4):1090-1092. 17. Béland-Bonenfant S, Paque e M, Fan no M, et al. Montreal-FH-SCORE predicts coronary artery calcium score in pa ents with familial hypercholesterolemia. CJC Open. 2021;3(1):41-47. 18. Mszar R, Nasir K, Santos RD. Coronary artery calci ca on in familial hypercholesterolemia: an opportunity for risk assessment and shared decision making with the power of zero? Circula on. 2020;142(15):1405-1407. 19. Lui DTW, Lee ACH, Tan KCB. Management of familial hypercholesterolemia: current status and future perspec ves. J Endocr Soc. 2021;5(1):bvaa122. 20. Kaufman TM, Warden BA, Minnier J, et al. Applica on of PCSK9 inhibitors in prac ce. Circ Res. 2019;124(1):32-37. 21. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of non-sta n therapies for LDL-cholesterol lowering in the management of atherosclero c cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(14):1785-1822. 22. Brown EE, Sturm AC, Cuchel M, et al. Gene c tes ng in dyslipidemia: a scien Associa on. J Clin Lipidol. 2020;14(4):398-413.

c statement from the Na onal Lipid

23. Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal an bodies by iden fying pa ents most likely to bene t. J Clin Lipidol. 2019;13(4):525-537. 24. Johansen AK, Bogsrud MP, Roeters van Lennep J, et al. Long term follow-up of children with familial hypercholesterolemia and rela vely normal LDL-cholesterol at diagnosis. J Clin Lipidol. 2021;15(2):375-378.

25. Sturm AC, Knowles JW, Gidding SS, et al. Clinical gene c tes ng for familial hypercholesterolemia: JACC Scien Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680.

CLINICAL RESOURCE CENTER™ Clinical Practice Guidelines Genetic testing in dyslipidemia: A scienti ic statement from the National Lipid Association. Brown EE, Sturm AC, Cuchel M, et al. J Clin Lipidol. 2020;14(4):398-413. https://www.lipidjournal.com/article/S1933-2874(20)30081-7/fulltext

The agenda for familial hypercholesterolemia: A scienti ic statement from the American Heart Association. Gidding SS, Champagne MA, de Ferranti SD, et al. Circulation. 2015;132(22):2167-2192. https://www.ahajournals.org/doi/10.1161/cir.0000000000000297

Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Goldberg AC, Hopkins PN, Toth PP, et al. J Clin Lipidol. 2011;5(suppl 3):S1-S8. https://www.lipidjournal.com/article/S1933-2874(11)00562-9/fulltext

Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020 Executive Summary. Handelsman Y, Jellinger PS, Guerin CK, et al. Endocr Pract. 2020;26(10):1196-1224. https://www.endocrinepractice.org/article/S1530-891X(20)48204-7/fulltext

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modi ication to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Mach F, Baigent C, Catapano AL, et al. Eur Heart J. 2020;41(1):111-188.

https://academic.oup.com/eurheartj/article/41/1/111/5556353

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Eur Heart J. 2013;34(45):3478-3490. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844152/

Enhancing the value of PCSK9 monoclonal antibodies by identifying patients most likely to bene it. A consensus statement from the National Lipid Association. Robinson JG, Jayanna MB, Brown AS, et al. J Clin Lipidol. 2019;13(4):525-537. https://www.lipidjournal.com/article/S1933-2874(19)30181-3/fulltext

Clinical genetic testing for familial hypercholesterolemia: JACC Scienti ic Expert Panel. Sturm AC, Knowles JW, Gidding SS, et al. J Am Coll Cardiol. 2018;72(6):662-680. https://www.sciencedirect.com/science/article/pii/S0735109718350654?via%3Dihub

Lipid measurements in the management of cardiovascular diseases: practical recommendations. A scienti ic statement from the National Lipid Association Writing Group. Wilson PWF, Jacobson TA, Martin SS. et al. J Clin Lipidol. 2021. [In press.] https://www.sciencedirect.com/science/article/pii/S1933287421002452

Patient and Caregiver Resources American Heart Association https://www.heart.org/en/health-topics/cholesterol/causes-of-high-cholesterol/familialhypercholesterolemia- h

FH Foundation https://the hfoundation.org/

National Lipid Association

https://www.lipid.org/

Suggested Readings A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. Ajufo E, deGoma EM, Raper A, Yu KD, Cuchel M, Rader DJ. Genet Med. 2021;23(9):1697-1704. https://www.nature.com/articles/s41436-021-01192-z

Bempedoic acid plus ezetimibe ixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Ballantyne CM, Laufs U, Ray KK, et al. Eur J Prev Cardiol. 2020;27(6):593-603. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153222/

The lifelong burden of homozygous familial hypercholesterolemia. Banerjee A, Alothman L, Couture P, et al. Can J Cardiol. 2019;35(10):1419.e1-1419.e4. https://www.onlinecjc.ca/article/S0828-282X(19)30425-8/fulltext

Montreal-FH-SCORE predicts coronary artery calcium score in patients with familial hypercholesterolemia. Béland-Bonenfant S, Paquette M, Fantino M, et al. CJC Open. 2021;3(1):41-47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801205/

Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Bianconi V, Banach M, Pirro M. Trends Cardiovasc Med. 2021;31(4):205-215. https://www.sciencedirect.com/science/article/pii/S1050173820300414?via%3Dihub

E icacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH trial. Blom DJ, Harada-Shiba M, Rubba P, et al. J Am Coll Cardiol. 2020;76(2):131-142. https://www.sciencedirect.com/science/article/pii/S073510972035316X?via%3Dihub

Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia? Brandts J, Dharmayat KI, Ray KK, Vallejo-Vaz AJ. Curr Opin Lipidol. 2020;31(3):111-118.

https://journals.lww.com/co-lipidology/Abstract/2020/06000/ Familial_hypercholesterolemia__is_it_time_to.2.aspx

PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study. Daniels S, Caprio S, Chaudhari U, et al. J Clin Lipidol. 2020;14(3):322-330.e6. https://www.lipidjournal.com/article/S1933-2874(20)30044-1/fulltext

Long-term safety, tolerability, and e icacy of evolocumab in patients with heterozygous familial hypercholesterolemia. Hovingh GK, Raal FJ, Dent R, et al. J Clin Lipidol. 2017;11(6):1448-1457. https://www.lipidjournal.com/article/S1933-2874(17)30448-8/fulltext

Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Ito MK, Watts GF. Drugs. 2015;75(15):1715-1724. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611011/

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Kastelein JJP, Ginsberg HN, Langslet G, et al. Eur Heart J. 2015;36(43):2996-3003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644253/

Management of familial hypercholesterolemia: current status and future perspectives. Lui DTW, Lee ACH, Tan KCB. J Endocr Soc. 2021;5(1):bvaa122. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059332/

Familial hypercholesterolemia: new horizons for diagnosis and e ective management. Mytilinaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS. Front Pharmacol. 2018;9:707. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052892/

Cascade screening and treatment initiation in young adults with heterozygous familial hypercholesterolemia. Peterson AL, Bang M, Block RC, Wong ND, Karalis DG. J Clin Med. 2021;10(14):3090. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306062/

Prevention of atherosclerotic cardiovascular disease in children with familial hypercholesterolemia. Peterson AL, McNeal CJ, Wilson DP. Curr Atheroscler Rep. 2021;23(10):64.

https://link.springer.com/article/10.1007%2Fs11883-021-00959-8

Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Raal FJ, Honarpour N, Blom DJ, et al. Lancet. 2015;385(9965):341-350. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61374-X/fulltext

Inclisiran for the treatment of heterozygous familial hypercholesterolemia. Raal FJ, Kallend D, Ray KK, et al. N Engl J Med. 2020;382(16):1520-1530. https://www.nejm.org/doi/full/10.1056/NEJMoa1913805

Evinacumab for homozygous familial hypercholesterolemia. Raal FJ, Rosenson RS, Reeskamp LF, et al. N Engl J Med. 2020;383(8):711-720. https://www.nejm.org/doi/full/10.1056/NEJMoa2004215

Familial hypercholesterolemia—epidemiology, diagnosis, and screening. Singh S, Bittner V. Curr Atheroscler Rep. 2015;17(2):482.

https://link.springer.com/article/10.1007%2Fs11883-014-0482-5

CME POSTTEST

In order to receive credit for this activity, the participant must direct their web browser to www.ExchangeCME.com/FHeHealth to complete the preactivity questionnaire, score 75% or better on the posttest, and complete the program evaluation.