Homozygous familial hypercholesterolemia (HoFH) is a rare metabolic disorder of mainly autosomal-dominant inheritance that causes extremely high low-density lipoprotein (LDL) cholesterol levels (Rosenson, 2021). Affected individuals show elevated LDL cholesterol levels from birth, which leads to premature atherosclerotic cardiovascular disease (ASCVD). Therefore, the early detection of this condition is critical to prevent early morbidity and mortality (Kayikcioglu et al., 2014; Zhang et al., 2020; Tokgozoglu and Kayikcioglu, 2021). At least four genes are associated with familial hypercholesterolemia (FH), including LDLR, APOB, PCSK9, and LDLRAP1, with phenotypic variations (Prince et al., 2013; Chemello et al., 2021; Tokgozoglu and Kayikcioglu, 2021). In most cases, the underlying mutation is in LDLR, which is associated with typical LDL cholesterol levels >500 mg/dl in patients with HoFH. Due to absent or defective LDL-receptor activity, individuals with HoFH are resistant to conventional lipid-lowering therapy (LLT) targeting LDL-cholesterol clearance by upregulating LDL receptors. Therefore, LDL apheresis is the most effective treatment for these patients (Kayikcioglu et al., 2018). However, the semi-invasive and time-consuming nature of apheresis is the major obstacle leading to decreased quality of life, increased risk of depression, and deterioration in mental status, leading to high treatment refusal and low adherence (Kayikcioglu et al., 2019; Tunçel et al., 2020). Therefore, effective pharmacotherapies with long-term safety are needed for patients with HoFH.

Lomitapide is a microsomal triglyceride transfer protein (MTTP) inhibitor that reduces LDL cholesterol levels through LDL receptor-independent pathways by directly decreasing apoprotein (Apo)-B levels (Cuchel et al., 2013). Herein, we present two patients with HoFH on long-term, low-dose lomitapide without drug adverse effects but different atheroma courses despite similar baseline LDL cholesterol levels.

Both patients were undergoing long-term follow-up at the Ege University Medical School, Department of Cardiology, Lipid Clinic. They were selected by the means of need and after receiving consent for the compassionate use of lomitapide as an add-on therapy. The clinical characteristics of the patients before and after lomitapide therapy are shown in Table 1. Figure 1A,B depicts the timeline of the case symptoms, diagnosis, and management.

We present two real-life cases of HoFH with completely different disease courses after the commencement of lomitapide therapy. Case 1 demonstrated that long-term effective LLT with low-dose lomitapide combined with apheresis safely prevented the progression of atheroma both in coronary and vascular territories and retarded the progression of aortic stenosis. However, Case 2 showed a completely different course, with significant progression of his coronary lesions and aortic involvement. The patient had to undergo re-operation despite similar baseline LDL-cholesterol levels to those in Case 1. The difference between these patients’ disease courses suggests the importance of adherence to therapy for the clinical success of therapy.

Lomitapide is a new-generation potent lipid-lowering agent that acts independently of LDL receptors. Lomitapide inhibits MTTP, a cellular protein that transports neutral lipids between membrane vesicles and acts as a chaperone for the synthesis of apoB-containing triglyceride-rich lipoproteins. Lomitapide has a critical role in the assembly and secretion of apoB-containing lipoproteins in the liver and intestines (Hussain et al., 2012). Thus, lomitapide, besides triglycerides, effectively reduces LDL-cholesterol levels in patients who are lacking or have mutant LDLR. Lomitapide has been approved by the Food and Drug Administration as a lipid-lowering agent for patients with HoFH as an adjunct to standard LLT and by the European Medicines Agency for patients treated with standard LLT with or without apheresis.

Clinical evidence indicates lomitapide as a potent LDL-receptor-independent agent that has made it possible for patients with HoFH to reach their LDL-cholesterol goals. The phase 3 open-label dose-escalation trial demonstrated that lomitapide at maximal-tolerated doses (5–60 mg/day) reduced LDL-cholesterol by 50% at 26 weeks when added to the standard of care including lipid apheresis in 29 patients with HoFH (Cuchel et al., 2013). Moreover, long-term lomitapide treatment (range 2.1–5.7 years) with a median daily dose of 40 mg reduced LDL-cholesterol levels by an average of 45.5% in 19 patients with HoFH (Blom et al., 2017). During the 246-week therapy, 14 (74%) patients achieved the LDL-cholesterol target of 100 mg/dl and 11 (58%) patients reached the target of 70 mg/dl on at least 1 occasion. We observed a 31% additional reduction in LDL-cholesterol after 1 month of very low-dose (5 mg/day) lomitapide and 49% at the end of 6 months of therapy for a dose of only 20 mg/day in Case 1. In Case 2, the LDL-cholesterol levels were reduced by an additional 27% and 49% for 5 and 20 mg daily doses of lomitapide at the end of 1 and 6 months, respectively. Due to the effective reductions in LDL-cholesterol levels, we decreased the frequency of the apheresis sessions to every 2 months. The LDL-cholesterol reductions achieved in our cases are consistent with those in an HoFH case series reporting >50% reductions for doses of 10–40 mg/day in real-life settings (Stefanutti et al., 2016), which likely led to clinically significant reductions in ASCVD. Consequently, Case 1, who showed a consistent reduction of LDL-cholesterol levels, showed no ASCVD events and no atheroma progression. However, Case 2 showed a different course, with atherosclerosis progression during the 5-year therapy. The difference in therapy adherence was likely the major explanation for the diverse disease courses after lomitapide therapy in our patients. Adherence to LLT favors the survival of patients with ASCVD (Dopheide et al., 2021). Case 1 was adherent since the first dose of therapy. However, in Case 2, the first attempt to use lomitapide was not successful as the patient declined its use due to weight loss; another major obstacle was non-compliance to the low-fat diet, which is a requirement for lomitapide use. After 3 years, we re-introduced the drug. While he was adherent to the low-fat diet, the patient had many excuses for his lack of therapy adherence, likely due to his impulsive behaviors. Barratt impulsivity Scale 11 (Tamam et al., 2013) demonstrated the high impulsivity of Case 2 and the low impulsivity of Case 1. Treatment adherence is inversely related to impulsive and compulsive behaviors (López-Torrecillas et al., 2021).

Hepato-steatosis and liver-enzyme elevation are well-known phenomena associated with lomitapide treatment. However, none of these were observed in either of our patients with the long-term use of lomitapide at doses lower than those used in clinical trials. The only adverse effect was the weight loss reported by Case 2. These findings suggest that most of the adverse events can be avoided by lowering the dosing of lomitapide, as assessed by the LOWER study, in which the long-term (5-year) follow-up of patients on lomitapide (10–20 mg/dl) showed significantly lower adverse event rates compared to the results of the Phase-3 study conducted with doses of 40–60 mg/dl (Underberg et al., 2020). Furthermore, the 20 mg daily dose of lomitapide effectively reduced LDL-cholesterol levels almost to the targets in Case 1 in the present study. Increasing the dose to 40 mg likely would have allowed us to stop apheresis; however, as the patient insisted on apheresis therapy, we continued with 20 mg lomitapide combined with bi-monthly apheresis for >7 years without adverse effects. Low-dose lomitapide plus conventional therapy (statin and ezetimibe) with a decreased apheresis frequency probably increased the adherence to long-term therapy besides efficient LDL-lowering. Similarly, the use of combination therapy was associated with a higher proportion and greater odds of achieving the therapeutic LDL goals of <70 mg/dl and <55 mg/dl,, particularly with the combination of five drugs in the HICC registry (Vallejo-Vaz et al., 2021).

An important aspect of Case 1 in this study is the stabilized course of the aortic atheroma. In patients with late apheresis initiation after 8–10 years of age, the progression of aortic atheroma to stenosis reportedly cannot be prevented even if the LDL goals are attained (Cuchel et al., 2014; Kayikcioglu et al., 2018; Kayikcioglu, 2021). However, in Case 1, after commencing lomitapide use, the aortic involvement of the valvular stenosis and aortic plaques remained stable. This is also contrary to our clinical experience that despite meeting the LDL goals, children with late-onset apheresis therapy (after 8 years of age) show a gradual progression of aortic valve sclerosis or mild stenosis to moderate and severe stenosis.

In addition, our experiences with both of these patients call attention to lipid apheresis as a treatment difficult to access during the pandemic. Thus, novel effective LDL-lowering agents such as oral lomitapide may be useful for patients with HoFH during lockdowns due to pandemics or any other disaster that could disrupt access to apheresis as a hospital-based therapy (Kayikcioglu et al., 2020). Moreover, apheresis cessation or decreased frequency with an effective LDL-lowering agent will improve the psychosocial wellbeing of patients. We previously documented that apheresis as a semi-invasive, time-consuming therapy leads to a decreased quality of life, increased risk of depression, and deterioration in mental status, which lead to high refusal and low adherence rates (Kayikcioglu et al., 2019; Tunçel et al., 2020) noticeably leading to undertreatment of patients with HoFH, consequently affecting ASCVD outcomes.

Although both patients were phenotypically HoFH with untreated LDL-cholesterol levels >500 mg/dl, xanthomas appearing at early ages, and parental clinical features of heterozygous FH, Case 1 was heterozygous and Case 2 was homozygous for LDLR mutations. In addition to standard genetic analysis of the four associated genes, this study is the first to study MTTP in patients with HoFH. Loss-of-function mutations within MTTP result in severe autosomal recessive diseases, causing ataxia, failure to thrive, steatorrhea, and muscle weakness known as abetalipoproteinemia (Hussain et al., 2012). However, gain-of-function mutations in MTTP are not yet well understood. We identified several variants in both patients that may alter lipid levels or affect the clinical efficacy and adverse reactions to lomitapide.

The cases presented have some limitations and strengths. The evaluation of only five genes affecting LDL-cholesterol levels might be a limitation as other genes may explain the severe FH phenotype of the patients, especially in Case 1. However, the evaluation of MTTP variants is an important strength as these are the first case presentations of HoFH with MTTP variants. Detailed long-term follow-up of the cases and evaluation of impulsivity are additional strengths that allow the evaluation of adherence, clinical course, and the associated factors. Moreover, Case 1 is the first reported case to show the cessation of aortic atheroma progression despite the late onset of apheresis therapy, suggesting the importance of effective LDL-cholesterol lowering in combination with lomitapide and apheresis. Moreover, the comparison of two HoFH patients with similar lipid profiles at baseline and who received the same therapy allowed the assessment of the impact of adherence to therapy.

In conclusion, long-term, low-dose lomitapide was an effective and well-tolerated adjunct to conventional LLT and lipid apheresis in real life. Adherence to lomitapide and a low-fat diet in addition to standard LLT with decreased apheresis frequency appeared to be associated with more effective and safer management of HoFH and prevented the progression of atheroma burden in both the coronaries and aorta and regression in CIMT and ATT. Further studies are needed to illuminate the role of gain-of-function mutations in MTTP on lipid levels and response to lomitapide in patients with HoFH.