A narrative review of treatment modalities for familial hypercholesterolemia

J Atherosclerosis Prev Treat. 2023 Sep-Dec;14(3):128-137| doi:10.53590/japt.02.1054


Georgios Samprokatsidis, Christina Antza, Despoina Frangou, Vasilios Kotsis

3rd Department of Internal Medicine, General Hospital Papageorgiou, Aristotle University of Thessaloniki




Familial Hypercholesterolemia (FH), a commonly missed disorder in a patient with abnormalities in lipid metabolism is described as a heritable disorder presenting elevated LDL cholesterol and lipid deposition in various tissues. This contributes to the early development of manifestations of atherosclerotic disease with the preterm occurrence of severe cardiovascular events. Apparently, decision-making is a strenuous effort and many individuals are underdiagnosed. FH affects LDL receptor and its function plays a critical role in the mechanism of many therapeutic modalities, thus alternative pathways must also be considered. This review addresses the main options of care in individuals with familial hypercholesterolemia along with unconventional drugs like mipomersen, inclisiran, lomitapide, gamcabene, and ANGLT3 inhibitors which have yielded important results for disease management.

Key words: Familial hypercholesterolemia, LDLR dependent, LDLR independent

Corresponding author: Georgios Samprokatsidis, M. Fotiou 9A, Kilkis 61100, e-mail: georgesabro@gmail.com

Submission: 05.08.2023, Acceptance: 13.11.2023


Familial Hypercholesterolemia (FH) is a well-known but rather underdiagnosed primary disorder of lipoprotein metabolism that is inherited in an autosomal co-dominant pattern and it is the result of gene-mutations that encode the LDL receptor (often termed as autosomal dominant hypercholesterolemia type 1 or ADH1), apolipoprotein B (often termed as autosomal dominant hypercholesterolemia type 2 or ADH2) or proprotein convertase subtilisin/kexin type 9 or PCSK9 (often termed as autosomal dominant hypercholesterolemia type 3 or ADH3). Those affected can have defects in one or both alleles of a gene referred to as heterozygotes or homozygotes respectively. The latter is further classified as receptor-negative with no detectable functional LDL receptors and receptor defective with a very low but present amount of functional LDL receptor. There is also a rare form of the disease that is inherited in an autosomal recessive manner if a mutation occurs in the LDRL adaptor protein1. Among the main types of defects described, mutations in the LDL receptor gene are the most common resulting in 80-85% of cases, while those in the apolipoprotein B100 binding site contribute to about 5-10%, while in the PCSK9 gene generally rarely occur in about 2% of cases2.

FH is a disorder estimated to affect between 14 and 34 million people worldwide with a prevalence of 1 in 311 for heterozygotes (HeFH) and 1 in 200.000-300.000 for homozygotes (HoFH) with the highest rates being among Christian Lebanese, South Afrikaners, Ashkenazi Jews and French Canadians in Quebec3-6. It is estimated that patients who receive no treatment for HeFH, appear to have an increased probability of experiencing their first coronary event 20 or more years earlier than the general population while in HoFH coronary events can occur even in childhood or adolescence7.

Clinical suspicion of FH should be considered upon encountering a patient presenting with tendon xanthomas, xanthelasmas, and arcus cornealis and/or a lipid profile of high LDL-C >190mg/dl and total cholesterol with or without hypertriglyceridemia8. As of today, there are no universally agreed-upon criteria for the diagnosis of the disease and thus it is carried out on clinical grounds along with the utilization of certain diagnostic tools such as the Dutch Lipid Clinic Network criteria, the Simon Broome system, the US Make Early Diagnosis to Prevent Early Death or MEDPED, the National Lipid Association expert panel recommendations and lately the American Heart Association criteria. Every approach varies from each other but all agree that LDL-C levels are mandatory to establish a diagnosis9. To accompany this a solid screening strategy is fundamental to establish early detection of the illness because if one of the parents is heterozygous for FH then 50% of the siblings are anticipated to be affected as well, while if both are heterozygous then there is a 25% and 50% chance of contracting HoFH and HeFH, respectively10,11. Once a possibly affected individual is encountered, genetic testing and subsequent cascade screening of any corresponding relative is advised, starting with first-degree relatives12,13.


According to current EAS/ESC guidelines individuals with FH are stated as high or very high risk depending on the existence of atherosclerotic cardiovascular disease or any other major risk factor. Therefore, an LDL reduction of ≥50% from baseline and a target LDL of <70mg/dl for high risk and <55mg/dl for very high risk individuals with FH, respectively, is advised14,15. For every mmol/l of LDL reduction an additional reduction of 22% can be achieved16.Patient management begins with lifestyle modifications and the implementation of an appropriate diet as early as possible under proper guidance by an experienced nutritionist, accompanied by weight maintenance with frequent physical exercise of more than one hour for children17.


The cornerstone of treatment in both HoFH and HeFH remain the well-known statins or 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors which inhibit sterol synthesis in the liver and enhance LDL receptor affinity, whereas upregulating LDL degradation18. Simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin are approved for use among many countries19,20. It is advised that therapy initiation at an earlier stage is of extreme benefit since the risk of experiencing a major cardiovascular event is about ten times lower in those individuals over an approximately 10-year period of treatment21,22. In children affected by FH, treatment with statins from 8-10 years of age is advised starting at low doses which could be increased to reach target values23. In the pediatric population, pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin have been studied, at a maximum dose of 40mg for pravastatin and simvastatin, 20mg for rosuvastatin and atorvastatin and at 80mg for fluvastatin. Pitavastatin has also been studied in children with FH and has gained approval by the FDA for children ≥8 years of age with HeFH24-26. Rosuvastatin lowers the development of increased intima-media thickness (IMT) over a 2-year period and a similar effect in adults can be achieved with atorvastatin within the same time frame. Moreover, statin monotherapy in heterozygous adults might not reach the advised LDL levels by the guidelines and adherence to therapy can be poor (about 50% of appropriate patients)27. An important highlight over the usage of statins in pregnancy is the withdrawal of their contraindication in pregnancy by the FDA for pregnant women or for those considering pregnancy. As it became evident from a number of studies investigating the safety of statins, the rate of miscarriages, congenital disturbances, median gestational age at birth or weight at birth did not show significant increases with no reports on teratogenic effects in the first trimester, though preterm birth was noted more frequently28. It is of interest to be mentioned that adverse events in pregnancy were noted more commonly with lipophilic statins than with hydrophilic probably due to their potential passage through the placenta29. A concerning aspect of statin treatment in an individual with HoFH is the amount of LDL receptors that can be recruited to perform their respective actions, which in receptor-negative patients can possibly render statins as well as PCSK9 inhibitors an effortless choice in reducing LDL-C30. Despite that, statins remain the first choice of treatment and they are generally well tolerated, with reports of elevated aminotransferase levels, liver dysfunction and rhabdomyolysis as the most common adverse effects, though they are extremely rare with a rise of aminotransferase values by a factor of 3 in less than 1% of adults on statin treatment and a risk of 0,08% to 0,09% of rhabdomyolysis in children with FH. A particular consideration is made upon the possible effects of statins in growth and maturation, both of which are still under investigation31.


Ezetimibe is a selective inhibitor of intestinal cholesterol absorption that binds to Niemann-Pick C1 Like protein or NPC1L1 and prevents absorption of biliary and dietary cholesterol by the intestine. It has been evaluated as monotherapy in HeFH with a reductive potential of 25,7% in LDL-C or in combination with statins like simvastatin with up to 49,1% reduction in LDL-C. Ezetimibe is generally well tolerated with reported adverse effects displaying elevated aminotransferase levels or myalgias with no reported alterations in growth, maturation or steroid hormones32-34. Furthermore, it is common for increased-risk individuals who are candidates for PCSK9 inhibitor therapy to combine all three medications in order to accomplish a favorable outcome. In actual fact, it is of value to mention that if ezetimibe is withdrawn from this triple regimen it could have a significant effect on LDL-C in certain patients35.

PCSK9 Inhibitors

Proprotein convertase subtilisin/kexin type 9 or PCSK9 is an enzyme critically involved in the processing of the LDL receptor by binding with the epidermal growth factor-like repeat A (EGF-A) part of the LDL receptor and the resulting complex is redirected to the lysosomes in the hepatocytes for degradation, thus interfering with recycling of the receptor on the surface of the cell. Alternatively, when the receptor binds with LDL it is released from the surface of the hepatocyte and enters the endosome, which in turn dissociates and breaks down LDL under acidic conditions and the receptor returns to repeat this process (about 150 times) further removing LDL off of the circulation. The above-mentioned process is the basis of the mode of action of PCSK9 inhibitors with their main approved representatives being evolocumab at a dose of 140mg every 2 weeks or 420mg monthly and alirocumab at a dose of 75mg every 2 weeks or 300mg every 4 weeks36,37. These agents are human monoclonal antibodies, a fact which is essential since, bococizumab a humanized inhibitor of PCSK9 has been pulled over from clinical trials (SPIRE-1 and SPIRE-2) for its non-sustainable reduction of LDL due to neutralizing antibodies. The administration is carried out subcutaneously and at its maximum dose can decrease LDL-C by 60% in the plasma37,38. Evolocumab is an immunoglobulin G2(IgG2) and it has been studied in heterozygous familial hypercholesterolemia by the RUTHERFORD study with a mean decrease in LDL-C of 60,2% at weeks 10 and 12 of treatment and in homozygous familial hypercholesterolemia by the TESLA study with no decrease in LDL-C from double receptor negative defects and about 19,3% and 26,3% in four and two weeks, respectively suggesting the necessity of LDL receptor function for PCSK9 inhibitors to work39,40. Over and above that in the HAUSER-RCT study of a pediatric population from 10 to 17 years with HeFH evolocumab has shown a level of 38,3% decrease of LDL at 24 weeks, observed intensively at 22 weeks, in the TAUSSIG study, which involved HoFH and severe HeFH patients with a some of them on lipoprotein apheresis, there was no remarkable difference in LDL reduction between on and off apheresis patients but a portion could lower the frequency of the treatment or discontinue it. Lastly in the FOURIER study cardiovascular outcomes were addressed in high-risk individuals with known stable cardiovascular disease with a reduction of 15% in its primary endpoint41-43. Alirocumab has been investigated during the ODYSSEY study which utilized a wide spectrum of subjects namely in HeFH individuals with a reduction of 57,9% (ODYSSEY FH I) in one group and  51,4% in the other(ODYSSEY FH II) at week 24 and dosed 75mg every two weeks, in HeFH with LDL-C ≥ 160mg/dl with 39,1% reduction in a dose of 150mg every 2 weeks (ODYSSEY HIGH FH) and in the pediatric population aged 8-17 years with values of even 46% lower LDL (ODYSSEY KIDS)44-47. HoFH cases were assessed in the ODYSSEY HoFH trial, dosed at 150mg every 2 weeks with a mean 26,9% reduction in LDL at week 12 and high variability in among double receptor-negative variants. At this point, it is important to add that alirocumab exhibited an important reduction in ApoB, non-HDL, total cholesterol, and Lp(a) values48-50. Interestingly, these medications were not associated with myopathy or elevated liver enzymes, which is a common concern with statins. It can be stated also that the adverse effect profile includes injection-site reactions (3,8% with alirocumab and 2,1% with evolocumab) and a concern of anti-drug antibodies (0,5% for alirocumab in the ODYSSEY OUTCOMES trial and 0,3% for evolocumab in the FOURIER trial). Reports and concerns for neurocognitive impairments or fat-soluble vitamin loss have not been confirmed51,52.

Bempedoic Acid

Bempedoic acid is an orally administered compound that blocks adenosine triphosphate-citrate lyase (ACL) a key enzyme in cholesterol biosynthesis and as is the case with statins LDL receptors increase in number, resulting in a notable decline in LDL-C in the circulation. This medication is approved for use in HeFH, usually at a dose of 180mg daily with a half-life of 15-24 hours and it can be used in combination with ezetimibe for an additional LDL-lowering effect53. During the CLEAR HARMONY study, which evaluated safety and efficacy data during a 1-year interval, observed adverse effects were mainly nasopharyngitis, myalgia, upper respiratory tract infection, urinary tract infection, arthralgia, dizziness, muscle spasms, diarrhea and increase in the levels of uric acid but were also regarded as mild to moderate54-56. A rather interesting aspect of the medication is its specificity for the liver for its activation, avoiding skeletal muscle and related side effects. Therefore, it could be considered a good alternative to statins, especially in cases of intolerance57.

RNA targeting agents

The introduction of drugs that aim at the mRNA of genes that can cause disease and prevent them from translating into a protein is a rather novel concept but has shown significant results and there are mainly two categories of drugs that have been used, namely antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). ASOs are altered molecules of single-stranded DNA that bind with sense mRNAs in the nucleus or cytoplasm of the cell, are administered subcutaneously, and have a short time of distribution (less than an hour) with a prolonged lifespan intracellularly (about 2-4 weeks), while siRNAs are double-stranded RNA molecules that bind to the RNA-induced silencing complex (RISC) and incorporate their antisense strand into the complex to promote mRNA degradation58. Inclisiran is the approved main representative of siRNAs that targets synthesis of PCSK9 in the liver and is usually dosed twice annually. This method has, actually, shown promise through the ORION trial, in which heterozygous patients were administered 300mg of inclisiran sodium a 1,5ml subcutaneous injection on days 1, 90, 270 and 450 and resulted in 39,7% lowering of LDL, a mean absolute reduction of 59mg/dl in LDL cholesterol and a reduction of total cholesterol, non-HDL, triglycerides and Lp(a) along with a rise in HDL values, while side effects were mild to moderate, mostly attributed to injection site reactions59-61. Mipomersen is the main representative of ASOs, it targets apolipoprotein B100 mRNA for degradation, it is administered subcutaneously as a sodium formulation and its half-life is approximately 30 days62. In about 3-4 hours peak plasma concentrations are achieved and drug metabolism is carried out by endonucleases and exonucleases in a successive fashion without affecting cytochrome P450 metabolized drugs62. Regarding its effectiveness in FH, Phase II, and III trials have highlighted that in heterozygous individuals receiving doses of 200mg and 300mg with once-per-week dosing for 6 weeks there is a reduction of  23% and 33% in LDL-C, respectively. Assessment of HoFH individuals under mipomersen treatment showed that, of those who completed the assigned 26-week therapeutic period, a 25% reduction in LDL-C, 31% in Lp(a), and 17% in triglycerides was reached, though there was a substantial variability63. The safety profile of this medication contained mostly injection site reactions, due to the mode of administration and hepatic steatosis with an increase in transaminase levels but with no evidence of liver toxicity64. Unfortunately, mipomersen had its approval withdraw and is still not approved by the European Medicines Agency65.


Lomitapide, a recently approved orphan drug for HoFH, inhibits microsomal triglyceride transfer protein or MTP. This, consecutively prevents the assembly of VLDL in the liver, chylomicrons in the intestine along with LDL-C in an LDR-independent pattern. It is administered orally in addition to diet or other treatment modalities, beginning with a dose of 5mg and is up-titrated to a maximum dose of 60mg with a half-life of about 40 hours66. According to many studies, lomitapide can reduce LDL-C up to 40-50% independently of lipoprotein apheresis treatment with mainly gastrointestinal side effects such as diarrhea, increase in liver transaminases in some patients, and the possible appearance of liver steatosis as it was evident from cohorts that utilized ultrasound or MRI. Unfortunately, these studies represented a small number of patients due to the rarity of the disease but have since shown that for each millimole per liter of reduction in LDL-C the relative risk of mortality declined by 23%, the risk of a major cardiovascular event by 15% and mean life expectancy can rise to 5,7 more years if the drug was initiated at an age of 18 years or 6,7 years if it was started at birth67-69.


Gamcabene is an orally delivered orphan drug used for HoFH that blocks TG and cholesterol production in the liver as well as apoC-III synthesis, reducing LDL-C levels in an LDLR-independent manner70. It is used adjunctively with other lipid-reducing modalities as demonstrated by the COBALT study during which patients for 12-weeks were administered doses of 300mg, 600mg, and 900mg daily for 4 weeks each, achieving reductions in LDL-C of 26% at 300mg, 30% at 600mg and 29% at 900mg, while the only side effects shown were diarrhea, headache and a slight rise in serum creatinine. Most of these side effects were regarded as mild to moderate with good tolerance to the medication71. Currently, Gamcabene is not approved for in practice and further evaluation is needed72.

Angiopoietin-like protein 3 inhibitors

A meaningful addition is angiopoietin-like protein 3 (ANGPTL3) inhibitors a novel line of drugs that surfaced after the realization of several reduced lipid parameters in subjects carrying loss-of-function mutations in the ANGPTL3 gene73. ANGPTL3 is produced in the liver and inhibits endothelial and lipoprotein lipases, thus decreasing VLDL and HDL clearance, respectively74. This is the case with evinacumab, an approved human monoclonal antibody that targets this protein, decreasing LDL-C values by 47,1% as an intravenous infusion at a dose of 15mg/kg of body weight with good tolerance of the drug as was depicted by the ELIPSE HoFH trial75. Currently, an ASO targeting hepatic ANGPTL3 mRNA was being evaluated in the IONIS ANGPTL3-LRx phase 2 clinical trial but was discontinued due to a lack of a sufficient number of participants70,76.

Invasive Modalities

Many cases of FH fail to accomplish their expected target values of LDL-C pharmaceutically and as is the case with HoFH need to be referred for lipoprotein apheresis (LA) and, though controversial, liver transplantation86,87. LA is the extracorporeal selective elimination of apolipoprotein B-containing lipoproteins and the most efficacious way of care if conjointly with standard anti-lipidemic drugs for HoFH, achieving 45-76% reduction in LDL-C in a 2-4h lasting procedure which is performed every one or two weeks according to the severity of the disease. Nowadays, side effects occur in less than 5% and include severe hypotension, hypocalcemia, anemia, bleeding disorder, infections, allergies, and fistulas from the frequent usage of an access route86. Liver transplantation relies on the fact that about 75% of LDL receptors are located in the liver and replacement with fully an operational part can normalize cholesterol metabolism with about an 80% decrease in LDL-C.  However, it is questionable under what indications the procedure should be considered and it is an issue whether the benefit is higher than the risk both from the aspect of side effects from immunosuppression, possible rejection, or in some instances severe aortic stenosis and from how FH is viewed by its severity among other lethal diseases that do not have other alternatives given the low number of donors87,88.

Gene therapies

A rather novel concept in the therapeutic armament for FH are gene therapies, which currently utilize adeno-associated viruses(AAV), most commonly AAV-8, to deliver genes or amplify hepatocyte DNA in order to achieve LDLR expression89. These methods have been studied in clinical trials and it is important to address the clustered regularly interspaced short palindromic repeats(CRISPR)/ Cas9 system, which involves a gene editing system with Cas9 nuclease and a modified single guide RNA(sgRNA)90. DNA-break repair is carried out by either non-homologous end joining, which acts randomly or homology directed repair, which acts more precisely. Regarding FH, it has been utilized in mutant mice to increase LDLR expression by gene addition or inactivate PCSK9 or ANGPTL3. Nonetheless, satisfactory results have yet to be acquired. Potential barriers of these methods are the gene delivery system itself, immune response, persistence of genes and the possibility of these systems to reach their respective targets90,91(Table 1).


To sum up, various treatment options can be adopted to improve the clinical picture of individuals with FH but none can prevent manifestations of the disease. There are emerging modalities like gene therapy either with a viral vector, stem cells, or exosome-based ones, but they are still under development and careful supervision for potential side effects76,92. Decision-making on the best route of treatment is a debated concept since there are no unified consensus and diagnostic criteria among countries perplexing even further this situation. As such, statins are the first choice of treatment along with diet modifications which might be combined with ezetimibe, but in many cases, further measures must also be considered like PCSK9 inhibitors93. Novel treatments like mipomersen, inclisiran, lomitapide, gamcabene, and ANGLT3 inhibitors have shown substantial efficacy but their low cost effectiveness and lack of studies with a sufficient number of participants to support their use complicates medical decisions further. Accordingly, there is still room for innovation and development in this field with more studies over a stable diagnostic background.


I would like to express my profound gratitude to my supervisor Dr. Vasilios Kotsis and Christina Antza both of which provided me with insightful mentorship as well as the required guidance to approach this expansive subject matter a captivating and distinctive perspective. Dr. Georios Samprokatsidis bears responsibility regarding the accuracy and integrity of the data pertained in the present review.

Conflict of interest

There is no conflict of interest


  1. Rader DJ, Kathiresan S. Disorders of Lipoprotein Metabolism. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine, 20e [Internet]. New York, NY: McGraw-Hill Education; 2018. Available from: accessmedicine.mhmedical.com/content.aspx?aid=1183992782
  2. Zubielienė K, Valterytė G, Jonaitienė N, Žaliaduonytė D, Zabiela V. Familial hypercholesterolemia and its current diagnostics and treatment possibilities: A Literature Analysis. Vol. 58, Medicina (Kaunas, Lithuania). NLM (Medline); 2022.
  3. Toft-Nielsen F, Emanuelsson F, Benn M. Familial hypercholesterolemia prevalence among ethnicities—Systematic Review and Meta-Analysis. Front Genet [Internet]. 2022 Feb [cited 2023 Aug 01];13:840797. Available from: https://pubmed.ncbi.nlm.nih.gov/35186049/
  4. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: Meta-Analyses of 11 million subjects. J Am Coll Cardiol. 2020 May;75(20):2553–66.
  5. Zamora A, Masana L, Comas-Cufí M, Vila À, Plana N, García-Gil M, et al. Familial hypercholesterolemia in a European Mediterranean population—Prevalence and clinical data from 2.5 million primary care patients. J Clin Lipidol. 2017 Jul;11(4):1013–22.
  6. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct:277:483-92.
  7. Turgeon RD, Barry AR, Acpr P, Pearson GJ. Clinical review familial hypercholesterolemia review of diagnosis, screening, and treatment. Can Fam Physician. 2016 Jan;62(1):32-7.
  8. Casey Elkins BJ, Fruh S. Known genetic mutations in the Early diagnosis and treatment of familial hypercholesterolemia. The Nurse Practitioner [Internet]. 2019 [cited 2023 Aug 01];44. Available from: www.tnpj.com
  9. McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc [Internet]. 2019 Dec [cited 2023 Aug 01];8(24):e013225. Available from: https://pubmed.ncbi.nlm.nih.gov/31838973/
  10. Harada-Shiba M, Ohta T, Ohtake A, Ogura M, Dobashi K, Nohara A, et al. Guidance for pediatric familial hypercholesterolemia 2017. J Atheroscler Thromb [Internet]. 2018 Jun [cited 2023 Aug 01];25(6):539-53. Available from: https://pubmed.ncbi.nlm.nih.gov/29415907/
  11. Ison HE, Clarke SL, Knowles JW. Familial hypercholesterolemia. Synonyms: Familial hypercholesterolaemia, hyperlipoproteinemia type IIA. 2014.
  12. Louter L, Defesche J, Roeters van Lennep J. Cascade screening for familial hypercholesterolemia: Practical consequences. Atheroscler Suppl. 2017 Nov;30:77-85.
  13. Knowles JW, Rader DJ, Khoury MJ. Cascade screening for familial hypercholesterolemia and the use of genetic testing. JAMA. 2017 Jul;318(4):381-2.
  14. Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J [Internet]. 2023 Jul [cited 2023 Aug 01];44(25):2277–91. Available from: https://doi.org/10.1093/eurheartj/ehad197
  15. Rizos CV, Skoumas I, Rallidis L, Skalidis E, Tziomalos K, Garoufi A, et al. LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments. Int J Cardiol. 2021 Dec;345:119–24.
  16. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013 Dec;34(45):3478-90.
  17. Plana N, Rodríguez-Borjabad C, Ibarretxe D, Masana L. Familial hypercholesterolemia in childhood and adolescents: A hidden reality. Clin Investig Arterioscler. 2017 May-Jun:129-40.
  18. Malloy MJ, Kane JP. Agents used in dyslipidemia. In: Katzung BG, Vanderah TW, editors. Basic & Clinical Pharmacology [Internet].15th ed. New York, NY: McGraw-Hill; 2021 [cited YEAR MONTH DAY]. Available from: accessmedicine.mhmedical.com/content.aspx?aid=1176467148
  19. Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL, Goldstein LB, et al. Statin Safety and Associated Adverse Events A Scientific Statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):E38-1.
  20. Mortensen MB, Falk E, Schmidt M. Twenty-year nationwide trends in statin utilization and expenditure in denmark. Circ Cardiovasc Qual Outcomes [Internet]. 2017 Jul [cited 2023 Aug 01];10(7):e003811. Available from: https://pubmed.ncbi.nlm.nih.gov/28698192/
  21. Perez-Calahorra S, Laclaustra M, Marco-Benedí V, Lamiquiz-Moneo I, Pedro-Botet J, Plana N, et al. Effect of lipid-lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia. Atherosclerosis. 2019 May;284:245–52.
  22. Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, et al. 20-Year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019 Oct;381(16):1547–56.
  23. Mach F, Baigent C, Catapano AL, Koskina KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019 Nov;290:140-205.
  24. Radaelli G, Sausen G, Cesa CC, Santos F de S, Portal VL, Neyeloff JL, et al. Statin treatments and dosages in children with familial hypercholesterolemia: Meta-analysis. Arq Bras Cardiol. 2018 Dec;111(6):810-21.
  25. Harada-Shiba M, Kastelein JJP, Hovingh GK, Ray KK, Ohtake A, Arisaka O, et al. Efficacy and safety of pitavastatin in children and adolescents with familial hypercholesterolemia in Japan and Europe. J Atheroscler Thromb. 2018 May;25(5):422–9.
  26. Sunil B, Ashraf AP. Statin therapy in children. In: Abukabda A, Suciu M, Andor M, editors. Cardiovascular Risk Factors in Pathology [Internet]. Rijeka: IntechOpen; 2020 [cited 2023 Aug 01]; p. Ch. 5. Available from: https://doi.org/10.5772/intechopen.91367
  27. Pang J, Chan DC, Watts GF. The knowns and unknowns of contemporary statin therapy for familial hypercholesterolemia. Curr Atheroscler Rep. 2020 Sep;22(11):64.
  28. Poornima IG, Pulipati VP, Brinton EA, Wild RA. Update on statin use in pregnancy. Am J Med. Elsevier Inc. 2023 Jan; 136(1):12-14.
  29. Chang JC, Chen YJ, Chen IC, Lin WS, Chen YM, Lin CH. Perinatal outcomes after statin exposure during pregnancy. JAMA Netw Open [Internet]. 2021 Dec [cited 2023 Aug 01];4(12):e2141321. Available from: https://doi.org/10.1001/jamanetworkopen.2021.41321.
  30. Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, Ogura M, et al. Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. Vol. 25, Journal of Atherosclerosis and Thrombosis. J Atheroscler Thromb; 2018. Aug;25(8):751-70.
  31. Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, et al. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev [Internet]. 2017 [cited 2023 Aug 01]; 2017(7): CD006401. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483457/
  32. Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database Syst Rev [Internet]. 2018 Nov [cited 2023 Aug 01];11(11):CD012502. Available from: https://pubmed.ncbi.nlm.nih.gov/30480766/
  33. Kusters DM, Caceres M, Coll M, Cuffie C, Gagné C, Jacobson MS, et al. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia. J Pediatr. 2015 Jun;166(6):1377-84.e3.
  34. van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008 Oct;52:(17)1421-9.
  35. Hang S, Lazarte J, Hegele RA. Is Deprescription of ezetimibe safe in familial hypercholesterolemia patients taking evolocumab? CJC Open [Internet]. 2021 Dec [cited 2023 Aug 01];4(4):428-31. Available from: https://pubmed.ncbi.nlm.nih.gov/35495867/
  36. Ogura M. PCSK9 inhibition in the management of familial hypercholesterolemia. J Cardiol. 2018 Jan;71(1):1-7.
  37. Sabatine MS. PCSK9 inhibitors: Clinical evidence and implementation. Nat Rev Cardiol. 2019 Mar;16(3):155-65.
  38. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017 Apr;376(16):1527-39.
  39. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): A randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan;385(9965):331-40.
  40. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan;385(9965):341-50.
  41. Tomlinson B, Patil NG, Fok M, Kei Lam CW. Role of PCSK9 inhibitors in patients with familial hypercholesterolemia. Endocrinology and Metabolism. 2021 Apr;36(2):279–95.
  42. Santos RD, Ruzza A, Hovingh GK, Wiegman A, Mach F, Kurtz CE, et al. Evolocumab in pediatric heterozygous familial hypercholesterolemia. N Engl J Med. 2020 Oct;383(14):1317–27.
  43. Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, et al. Long-term evolocumab in patients with familial hypercholesterolemia. J Am Coll Cardiol. 2020 Feb;75(6):565–74.
  44. Pirillo A, Catapano AL, Norata GD. Monoclonal antibodies in the management of familial hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors. Curr Atheroscler Rep. 2021 Oct;23(12):79.
  45. Kastelein JJP, Ginsberg HN, Langslet G, Kees Hovingh G, Ceska R, Dufour R, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov;36(43):2996-3003.
  46. Kastelein JJP, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: Design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014 Jun;28(3):281-9.
  47. Daniels S, Caprio S, Chaudhari U, Manvelian G, Baccara-Dinet MT, Brunet A, et al. PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study. J Clin Lipidol. 2020 May-Jun;14(3):322-30.e5
  48. Thompson GR. PCSK9 Inhibitors for Homozygous Familial Hypercholesterolemia: Useful But Seldom Sufficient. J Am Coll Cardiol. 2020 Jul;76(2):143-5.
  49. Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, Kastelein JJP, Charng MJ, et al. Efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020 Jul;76(2):131–42.
  50. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013 Nov;128(19):2113-20.
  51. Kaddoura R, Orabi B, Salam AM. Efficacy and safety of PCSK9 monoclonal antibodies: An evidence-based review and update. J Drug Assess. 2020 Jan;9(1):129-44.
  52. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018 Nov;379(22):2097-107.
  53. Agarwala A, Quispe R, Goldberg AC, Michos ED. Bempedoic acid for heterozygous familial hypercholesterolemia: From bench to bedside. Drug Des Devel Ther. 2021 May;15:1955-63.
  54. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce ldl cholesterol. N Engl J Med. 2019 Mar;380(11):1022–32.
  55. Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LAT, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019 Nov;322(18):1780-8.
  56. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023 Apr;388(15):1353–64.
  57. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020 Apr;27(6):593-603.
  58. Chen R, Lin S, Chen X. The promising novel therapies for familial hypercholesterolemia. J Clin Lab Anal. 2022 Jul;36(7):e24552.
  59. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020 Apr;382(16):1520–30.
  60. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020 Apr;382(16):1507-19.
  61. Ray KK, Troquay RPT, Visseren FLJ, Leiter LA, Scott Wright R, Vikarunnessa S, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): Results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-19.
  62. Parham JS, Goldberg AC. Mipomersen and its use in familial hypercholesterolemia. Expert Opin Pharmacother. 2019 Jan;20(2):127-31.
  63. Bell DA, Hooper AJ, Watts GF, Burnett JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vasc Health Risk Manag. 2012:8:651-9.
  64. Astaneh B, Makhdami N, Astaneh V, Guyatt G. The effect of mipomersen in the management of patients with familial hypercholesterolemia: A systematic review and meta-analysis of clinical trials. J Cardiovasc Dev Dis. 2021 Jul;8(7):82.
  65. European Medicines Agency: EMA/177547/2013- Questions and answers on the refusal of the marketing authorization for Kynamro-Outcome of re-examination [Internet]. 2023 Jun [cited 2023 Aug 01]. Available from: https://www.ema.europa.eu/documents/smop-initial/questions-answers-refusal-marketing-authorisation-kynamro-outcome-re-examination_en.pdf
  66. Khoury E, Brisson D, Roy N, Tremblay G, Gaudet D. Review of the long-term safety of lomitapide: A microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia. Expert Opin Drug Saf. 2019 May;18(5):403-14.
  67. Stefanutti C. Lomitapide–a microsomal triglyceride transfer protein inhibitor for homozygous familial hypercholesterolemia. Curr Atheroscler Rep. 2020 Jun;22(8):38
  68. Kim SH, Baek SH. Lomitapide, relief pitcher for patients with homozygous familial hypercholesterolemia. Eur J Prev Cardiol. 2020 Jan;27(2):155-6.
  69. Mahzari M, Zarif H. Homozygous familial hypercholesterolemia (HoFH) in Saudi Arabia and two cases of lomitapide use in a real-world setting. Adv Ther. 2021 May;38(5):2159-69.
  70. Ajufo E, Rader DJ. New therapeutic approaches for familial hypercholesterolemia. Annu Rev Med. 2018 Jan 29:69:113-31.
  71. Gaudet D, Durst R, Lepor N, Bakker-Arkema R, Bisgaier C, Masson L, et al. Usefulness of gemcabene in homozygous familial hypercholesterolemia (from COBALT-1). Am J Cardiol. 2019 Dec;124(12):1876-80.
  72. Cesaro A, Fimiani F, Gragnano F, Moscarella E, Schiavo A, Vergara A, et al. New frontiers in the treatment of homozygous familial hypercholesterolemia. Heart Fail Clin. 2022 Jan;18(1):177-88.
  73. Bajaj A, Cuchel M. Advancements in the treatment of homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2022 Aug;29(8):1125-35.
  74. Lui DT, Lee AC, Tan KC, Tan K. Management of familial hypercholesterolemia: Current status and future perspectives. Journal of the Endocrine Society [Internet]. 2020 Aug [cited 2023 Aug 04]. Available from: https://academic.oup.com/jes/advance-article/doi/10.1210/jendso/bvaa122/5895281
  75. Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug;383(8):711–20.
  76. Li ZF, Wu NQ. The progression of treatment for refractory hypercholesterolemia: Focus on the prospect of gene therapy. Front Genet [Internet]. 2022 [cited 2023 Aug 04];13:911429. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218664/
  77. European Medicines Agency: EMA/258537/2021-Evkeeza: EPAR-Summary for the public [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/evkeeza-epar-summary-public_en.pdf
  78. European Medicines Agency: EMA/34440/2016-Lojuxta: EPAR-Summary for the public [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/lojuxta-epar-summary-public_en.pdf
  79. European Medicines Agency: EMA/561767/2020-Leqvio: Medicine overview [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/leqvio-epar-medicine-overview_en.pdf
  80. European Medicines Agency: EMA/65186/2020-Nilemdo: EPAR-Medicine overview [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/nilemdo-epar-medicine-overview_en.pdf
  81. European Medicines Agency: EMA/383130/2020-Praluent: EPAR-Medicine overview [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/praluent-epar-medicine-overview_en.pdf
  82. European Medicines Agency: EMA/5899/2022-Repatha: EPAR-Medicine overview [Internet]. 2023 June [cited 2023 Aug 09]. Available from: https://www.ema.europa.eu/en/documents/overview/repatha-epar-medicine-overview_en.pdf
  83. Gryskiewicz KA, Coleman CI, Gillespie EL, White CM. Cost-effectiveness analysis of combination Statin/Ezetimibe therapy for the treatment of elevated Low-Density lipoprotein cholesterol. Hospital Pharmacy. Wolters Kluwer Health, Inc. 2005;40(8):687-92.
  84. Chou R, Cantor A, Tracy Dana M, Jesse Wagner M, Azrah Ahmed M, Rongwei Fu B, et al. Evidence synthesis number 219 statin use for the primary prevention of cardiovascular disease in adults: A systematic review for the U.S. preventive services task force. JAMA. 2022 Aug 23;328(8):754-71.
  85. Vavlukis M, Vavlukis A. Adding ezetimibe to statin therapy: Latest evidence and clinical implications. Drugs Context [Internet]. 2018 Jul [cited 2023 Aug 09];7:212534. Available from: https://pubmed.ncbi.nlm.nih.gov/30023003/
  86. Kayikcioglu M. LDL Apheresis and Lp (a) Apheresis: A Clinician’s Perspective. Curr Atheroscler Rep. 2021 Feb;23(4):15.
  87. Ishigaki Y, Kawagishi N, Hasegawa Y, Sawada S, Katagiri H, Satomi S, et al. Liver transplantation for homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2019 Feb;26(2):121-7.
  88. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper fromthe Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014 Aug;35(32):2146-57.
  89. Zhao H, Li Y, He L, Pu W, Yu W, Li Y, et al. In Vivo AAV-CRISPR/Cas9-Mediated gene editing ameliorates atherosclerosis in familial hypercholesterolemia. Circulation. 2020 Jan;141(1):67-79.
  90. Jiang L, Wang LY, Cheng XS. Novel approaches for the treatment of familial hypercholesterolemia: Current status and future challenges. J Atheroscler Thromb. 2018 Aug;25(8):665-73.
  91. Canepari C, Cantore A. Gene transfer and genome edit-ing for familial hypercholesterolemia. Front Mol Med [Internet]. 2023 April [cited 2023 Sep 14]. Available from: https://doi.org/10.3389/fmmed.2023.1140997
  92. Li Z, Zhao P, Zhang Y, Wang J, Wang C, Liu Y, et al. Exosome-based Ldlr gene therapy for familial hypercholesterolemia in a mouse model. Theranostics. 2021 Jan;11(6):2953–65.
  93. Gossios T, Zografou I, Simoulidou V, Pirpassopoulou A, Christou K, Karagiannis A. Multimodal Treatment of Homozygous Familial Hypercholesterolemia. Curr Pharm Des. 2018 Oct;24(31):3616–21.