Multimodal Therapy Achieves Secondary Prevention LDL-C Targets in LDL-Receptor Null Homozygous Familial Hypercholesterolemia

Abstract

Background

Homozygous familial hypercholesterolemia is a rare condition most commonly associated with pathogenic variants in the LDLR gene that leads to mortality before age 20 if not treated.

Case Summary

A 4-year-old boy of Lebanese origin with multiple skin xanthomas was found to have untreated low-density lipoprotein cholesterol (LDL-C) of 1005 mg/dL (26 mM). Gene analysis revealed biallelic identical LDLR variants with <2% residual LDLR activity (LDLR-null).

Discussion

With combination therapy including maximum dose rosuvastatin, ezetimibe, plasma exchange, lomitapide, and evinacumab, guideline-recommended LDL-C of <70 mg/dL (1.8 mM) was achieved for secondary prevention of coronary disease. With this combined treatment, there has been no progression of his premature coronary heart disease.

Take-Home Messages

Effective treatment of homozygous familial hypercholesterolemia requires multimodal lipid-lowering therapies. With currently available treatments it is possible to achieve previously unattainable lowering of LDL-C to prevent vascular disease and the need for liver transplantation.

Graphical Abstract

History of Presentation

A 4-year-old boy of Lebanese origin was referred after being noted to have tuberous skin xanthomas on the hands, buttocks, and ankles. Family history was notable for his mother having untreated low-density lipoprotein cholesterol (LDL-C) of 376 mg/dL (9.74 mM) and his father having LDL-C of 256 mg/dL (6.65 mM). LDL-C on no treatment was 1005 mg/dL (26.0 mM). At initial presentation the patient had already been started on a fat-restricted diet plus rosuvastatin 20 mg and ezetimibe 10 mg daily, but LDL-C had decreased only to 862 mg/dL (22.4 mM). No corneal arcus, xanthelasma, or tendon xanthomas were found. Family history was also positive for hypercholesterolemia and premature coronary disease in multiple second-degree relatives.

Take-Home Messages

• •This case highlights the need for multimodal treatment to reduce severely elevated LDL-C in HoFH.
• •With combined treatment, guideline-recommended targets for LDL-C lowering can be achieved to prevent the progression of early-onset ASCVD in patients with HoFH.

Past Medical History

The patient was born following an unremarkable gestation. There was no other significant medical history.

Differential Diagnosis

The differential diagnosis for severe hypercholesterolemia included homozygous familial hypercholesterolemia (HoFH), sitosterolemia, and cerebrotendinous xanthomatosis. Sitosterolemia and cerebrotendinous xanthomatosis may exhibit xanthomas but are not typically associated with such high LDL-C.

Investigations

Genetic testing revealed the patient was homozygous for LDLR c2043C>A (p.Cys681), a common Lebanese variant resulting in truncated LDLR protein with <2% residual activity (“LDL receptor null”), on both LDLR alleles. The parents were not aware of being related. Carotid ultrasound revealed bilateral calcified plaques. Additional laboratory tests including lipoprotein(a) were unremarkable.

Management

In addition to statin and ezetimibe treatment, the patient was considered too small to initiate LDL apheresis or plasma exchange (PLEX). Liver transplant was considered, but owing to lack of experience with the procedure in children at our center and opposition by the parents it was not pursued. The family returned to Lebanon, and the patient remained on statin and ezetimibe treatment alone. At age 13, the patient and his family returned to Canada, at which time the rosuvastatin dose was increased to 40 mg daily, which along with ezetimibe 10 mg daily resulted in average LDL-C of 713 mg/dL (18.4 mM) and lowest LDL-C of 643 mg/dL (16.6 mM) (Figure 1). As expected, a trial of the PCSK9 inhibitor evolocumab resulted in no reduction in LDL-C owing to absence of LDLR activity. LDL apheresis was not available at our site. PLEX via bilateral antecubital vein access was initiated at 2-week intervals along with rosuvastatin and ezetimibe and was well tolerated. Following addition of PLEX, average LDL-C level achieved just before the next PLEX treatment was 449 mg/dL (11.6 mM) and minimum LDL-C was 344 mg/dL (8.93 mM). Addition of PLEX resulted in resolution of all skin xanthomas. Lomitapide was added to his treatment at age 16 and titrated gradually to 25 mg daily, which was generally well tolerated. Average LDL-C achieved before PLEX while taking lomitapide 25 mg daily was 141 mg/dL (3.62 mM) with minimum LDL-C of 107 mg/dL (2.79 mM). Based on the response to lomitapide, PLEX frequency was reduced to every 4 weeks. Alanine aminotransferase level increased from normal to an average 87 U/L or 1.75-fold above normal limits while on lomitapide 25 mg daily (normal <50 U/L, patient range 56-128 U/L). Liver ultrasound revealed new-onset mild fatty liver following addition of lomitapide, with no fibrosis by FibroScan (Echosens, Paris, France). At age 19, evinacumab 15 mg/kg delivered intravenously after PLEX every 4 weeks was added to all other treatments, which resulted in a further reduction of LDL-C to an average of 91 mg/dL (2.34 mM), and minimum LDL-C of 55 mg/dL (1.43 mM) 4 weeks following the last PLEX and evinacumab infusion (Figure 1). Time-averaged LDL-C just before PLEX in the year following addition of evinacumab was 76 mg/dL (1.97 mM) (a 45% further reduction in LDL-C compared with all other treatments) despite a reduction in lomitapide dose to 20 mg daily. Increases in LDL-C and alanine aminotransferase over time have been primarily related to less care with diet.

Figure 1.

Average LDL-C Values

Average low-density lipoprotein cholesterol (LDL-C) in either mg/dL (left y-axis) or mM (right y-axis) relative to the age of the patient at baseline and following addition of the indicated treatments. Drug doses are given in mg/day except evinacumab which is 15 mg/kg every 4 weeks. Black line indicates LDL-C when a treatment was initiated, and green line indicates the best LDL-C achieved while on the treatments indicated. Red line indicates recommended level of LDL-C for secondary prevention of atherosclerotic cardiovascular disease.^1,2

Outcome and Follow-Up

The patient has tolerated the treatments without any other side effects and is presently attending university. At age 16 he complained of mild chest tightness on exertion; coronary catheterization revealed a 40% stenosis of the left main coronary artery. Acetylsalicylic acid 81 mg daily was initiated following this finding. He has subsequently remained free of vascular symptoms. Coronary computed tomography (CT) angiography performed 6 months before addition of evinacumab revealed 1% to 24% noncalcified stenosis of the right, 25% to 49% calcified stenosis of the left main, and 25% to 49% noncalcified stenosis of D1 coronary arteries. Repeat coronary CT angiography 3.5 years after initiation of evinacumab revealed no significant plaque progression from the previous CT angiography (Figure 2).

Figure 2.

Coronary CT Angiography

Coronary computed tomography (CT) angiography coronal long axis section showing calcification of the left main coronary artery in 2020 and lack of progression of coronary calcification of this segment 4 years later in 2024.

Discussion

HoFH is a rare and severe genetic disorder occurring in approximately 1 in 350,000 individuals worldwide that leads to profoundly elevated LDL-C levels and a high risk of mortality owing to atherosclerotic cardiovascular disease (ASCVD) before age 20 if untreated.³ True HoFH as in this case involves identical pathogenic variants of both LDLR alleles (biallelic identical variants), with our patient having a common Lebanese LDLR variant resulting in <2% residual LDLR activity (LDLR null). As such, he has the most severe form of HoFH. In addition to confirmation of his genotype, the very high baseline LDL-C level, relatively weak response to combined statin plus ezetimibe, and absence of response to PCSK9 inhibitor all are consistent with absence of residual LDLR activity.⁴ For such patients, multiple modes of treatment are required to attempt to achieve recommended LDL-C targets for primary or secondary prevention of ASCVD. Whereas statins have the majority of their effect by stimulating upregulation of LDL receptors in the liver, they can still lower LDL-C in the absence of LDLR activity by limiting the availability of cholesterol for production of very low-density lipoproteins (VLDLs) by the liver, which are the precursor to LDL formation following hydrolysis of VLDL triglycerides.⁵ Ezetimibe similarly has the majority of its effect by stimulating LDLR expression in the liver, but has some effect on lowering LDL-C by reducing return of cholesterol from the intestine to the liver that can be used for VLDL production.⁵ In this case, rosuvastatin 40 mg and ezetimibe 10 mg daily lowered LDL-C to an average of 713 mg/dL (18.4 mM) or 30% below baseline levels. Whereas LDL apheresis is the preferred form of extracorporeal removal of plasma LDL-C, PLEX can be used in the absence of availability of this therapy and can achieve LDL-C lowering similar to LDL apheresis.⁶ PLEX reduces LDL-C acutely by removal of plasma in exchange for saline containing albumin, and is generally well tolerated.⁷ In this case addition of PLEX every 2 weeks to rosuvastatin and ezetimibe lowered LDL-C to an average of 449 mg/dL (11.6 mM) or 55% below baseline level.

Recent years have seen the introduction of novel treatments that can lower LDL-C in HoFH patients by mechanisms that do not require upregulation of the LDL receptor. Lomitapide inhibits microsomal triglyceride transfer protein, which reduces lipidation of apolipoprotein B in the liver and intestine, thereby inhibiting VLDL and chylomicron production.⁸ Potential side effects include hepatic steatosis and steatorrhea, particularly if dietary fat is not markedly restricted. In this case addition of lomitapide was quite well tolerated as long as dietary fat was restricted and lowered pre-PLEX LDL-C level down to an average of 141 mg/dL (3.65 mM), an additional 69% lowering of LDL-C compared with rosuvastatin/ezetimibe/PLEX and 86% compared to baseline LDL-C level. Liver ultrasound showed onset of mild hepatic steatosis following addition of lomitapide, but no evidence of liver fibrosis to date.

Evinacumab is a monoclonal antibody inhibitor of ANGPTL3, reduction of which allows lipoprotein lipase and endothelial lipase to increase hydrolysis and hepatic clearance of VLDL and VLDL remnants, thereby reducing conversion to LDL.⁹ Evinacumab lowers LDL-C in HoFH a further 43% on top of existing treatments in patients with null-null LDLR variants and 49% in patients with non-null LDLR variants, regardless of the initial LDL-C level.¹⁰ Inhibition of ANGPTL3 has also been shown to reduce hepatic steatosis,¹¹ with 1 report showing the elevated serum transaminases induced by lomitapide being reduced following addition of evinacumab.¹² These findings suggest combined use of lomitapide and evinacumab may mitigate the hepatic steatosis induced by lomitapide.

Additional LDL-C lowering with the use of lomitapide and/or evinacumab, or PCSK9 inhibitor when the patient has residual LDLR function, may allow reduction in the frequency or removal of the need for LDL apheresis or PLEX.¹³ In this case, a 3-month period off PLEX resulted in LDL-C increasing to an average of 102 mg/dL (2.63 mM) 4 weeks after evinacumab infusion compared with 57 mg/dL (1.48 mM) 4 weeks after PLEX followed by evinacumab infusion in the first months after evinacumab was added. To attempt to keep LDL-C under the target of <70 mg/dL (1.8 mM) recommended for secondary prevention of ASCVD in the most recent Canadian¹ and American² lipid guidelines, the decision was made jointly by the patient and his caregivers to continue PLEX every 4 weeks along with all the other treatments.

The availability of lomitapide and evinacumab along with his other treatments has therefore allowed a patient with the most severe form of HoFH to achieve LDL-C levels that were previously unattainable and, it is hoped, has halted the progression of his atherosclerosis. The patient has been fortunate to be receiving both lomitapide and evinacumab free of charge from the drug manufacturers under compassionate use programs. Despite both lomitapide and evinacumab being approved for use by Health Canada, the provincial medical services plan in British Columbia has declined to cover the cost of these medications, which combined would be more than $750,000 CAD annually. This underscores the high cost of treatment with these novel agents as well as PCSK9 inhibitors, which is prohibitive for a large number of patients with HoFH globally, even in wealthier countries. In situations in which these agents are not available or the cost not covered or if there is evidence of progression of coronary disease despite maximal therapy, liver transplantation to restore hepatic LDLR activity can still be considered as a last option.¹³

Conclusions

This case demonstrates the individual effectiveness of different modalities of LDL-C lowering in LDLR-null HoFH that can allow achievement of the LDL-C level recommended for secondary prevention of ASCVD. This multimodal treatment can extend the life span, decrease the burden of disease, and enable patients with HoFH to lead relatively normal lives.

Funding Support and Author Disclosures

Dr Alkhairy was a recipient of a Beedie Family Fellowship in Lipidology and Cardiovascular Disease Prevention. Dr Francis was a recipient of a Michael Smith Health Research/Providence Research Health Professional Investigatorship. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.