This long-term, real-world, retrospective case series of HoFH treatment demonstrates that lomitapide substantially reduced LDL-C and helped patients achieve LDL-C goals in a series of patients with a history of CVD as well as late diagnosis and treatment. These patients are reflective of other published HoFH cohorts [4, 5, 11,12,13,14], with five of six patients having CVD and a mean baseline LDL-C of 263.2 mg/dL on standard LLTs before treatment with lomitapide. Lomitapide doses were titrated according to clinical response in all patients, and there was no influence of LDLR genotype on LDL-C reduction associated with lomitapide, with similar reductions in both null/null and receptor defective patients, as expected. HDL-C levels remained stable or increased slightly throughout lomitapide treatment. Hepatic steatosis was either absent or mild to moderate after up to 7 years treatment with lomitapide. Hepatic elasticity remained normal in all but two older patients (> 70 years old) who had moderate hepatic stiffness at the last follow-up visit; however, one of the patients had no hepatic imaging data at baseline and therefore the hepatic stiffness before lomitapide treatment is unknown. Only one patient had a temporary increase in transaminases > 3x ULN, which was managed with a temporary dose reduction. The few adverse events reported were mild and manageable. Finally, improvements in CVD symptoms were observed in all patients with reported cardiovascular symptoms pre-lomitapide treatment, and there was stabilization or regression of CIMT and atheromatous plaques in all patients.

These effectiveness, tolerability and safety findings are in line with previous studies of lomitapide in patients with HoFH [4, 5, 11,12,13,14] and support that marked reductions in LDL-C can be achieved and gastrointestinal (GI) tolerability and long-term hepatic safety can be well managed in the real-world clinical setting. Long-term follow-up is usually not feasible in clinical trials, and the rarity of HoFH can make a powered clinical trial difficult to conduct. Therefore, real-world evidence such as this case series should be considered complementary to clinical trial data, with longer follow-up and the benefit of better reflecting the variability of patients, as seen in-clinic.

Although a causal relationship between lomitapide treatment and cardiovascular outcomes could not be determined in the present case series, it is of clinical interest to note the positive findings that there appeared to be no progression of atherosclerosis, with some signs of CIMT regression, which is the ultimate goal of aggressive lipid lowering in HoFH. It remains to be determined if these results represent a meaningful or sustainable outcome for future CVD events.

Due to the rarity of HoFH, it is difficult to analyze cardiovascular outcomes related to lomitapide treatment, but improvements in CVD symptoms and atherosclerotic burden has been observed in previous lomitapide studies [5, 11, 15, 16]. One retrospective real-world study found there were fewer cardiovascular events in patients treated with lomitapide compared with a cohort treated with lipoprotein apheresis [11], and another multinational real-world cohort study demonstrated a MACE incident rate of 7.4/1000 person-years in the two years after lomitapide treatment versus 21.2/1000 person-years in the two years prior, although this difference was not statistically significant [5].

In this analysis, lomitapide doses were up-titrated in all patients in 5 or 10 mg increments. The increments of 5 mg were used initially to reduce adverse events – particularly GI events – and find the lowest effective lomitapide dose to achieve LDL-C goals. Once the patients had demonstrated a good tolerance to the drug, the dose increments were increased to 10 mg, if necessary, to reach LDL-C goal. Four patients in this analysis were treated with a maximum dose of 20 mg or less, one patient received a maximum of 25 mg and one patient was able to increase their dose to 40 mg at last follow-up visit. With this flexible approach it was possible to minimize adverse events while aiming to treat to LDL-C goal. LDL-C was at, or close to, LDL-C goal at last follow-up for all patients, demonstrating that appropriate titration of lomitapide is important to enable patients to achieve their LDL-C goal, and that greater reductions in LDL-C are generally seen with more intensive lipid-lowering therapy. It should be noted that during the treatment of these patients, the LDL-C goals were < 100 mg/dL in patients without ASCVD (applicable to one patient in our analysis), or < 70 mg/dL in patients with ASCVD (applicable to the other five patients in our analysis), and therefore these were the clinical goals of the treating physicians [17]. In 2023, the updated EAS consensus statement recommended an LDL-C goal of < 70 mg/dL for adults with HoFH, or if patients have established ASCVD, or ASCVD risk factors such as elevated Lp(a) or diabetes mellitus, the recommended goal is < 55 mg/dL.3 However, despite combination therapy with LLTs and newer therapies available such as PCSK9 inhibitors, attainment of guideline-recommended goals remains rare [6].

The administration of lomitapide also resulted in a reduced necessity for other adjunctive LLTs. In the one case in this analysis where lipoprotein apheresis was administered, it was later discontinued at the patient’s request and in agreement with the physician, when LDL-C levels were substantially reduced. This is similar to findings from other studies with lomitapide, in which patients have either permanently discontinued or reduced the frequency of apheresis treatments whilst on lomitapide therapy [4, 5, 12]. Reasons for the other patients in this analysis not receiving apheresis included advanced age and comorbidity considerations, with lomitapide being preferred instead by both patient and physician. Apheresis can be time-consuming, uncomfortable and is associated with a reduced quality of life, including an increased risk of depression [18, 19]. Attending regular apheresis sessions also places a significant burden on patients in terms of travel time – which may also come with an associated financial burden – as well as interruption to normal activities and social life, and a potential impact on education and employment prospects [18,19,20]. The reduced use of apheresis in this case series is reflective of recent real-world data in HoFH showing 13–50% of patients are receiving apheresis, which is a smaller percentage than seen in the past [5, 11, 21].

In contrast to the limited use of apheresis, all patients in this analysis received PCSK9 inhibitors at some point; mostly at baseline, prior to lomitapide treatment. However, no patients remained on PCSK9 inhibitors at the final follow-up visit, with the reason for cessation being lack of effectiveness in all cases. This was despite some patients receiving PCSK9 inhibitor therapy for many months, and/or the dose being increased. In contrast, LDL-C levels were rapidly and substantially reduced upon initiation of lomitapide. The lack of effectiveness seen with PCSK9 inhibitors was not totally unexpected, as they rely on residual LDL receptor function [22] and have limited or no effect in patients with null mutations or mutations in LDLRAP1. [7, 23] However, some degree of response might be expected in five of the six patients with defective mutations [24, 25], so the fact that these therapies were also discontinued due to lack of effectiveness in defective/defective LDLR genotype patients is a notable finding. This, along with the greater convenience of oral therapies over injectable therapies and the high cost of PCSK9 inhibitors, also raises the question of the usefulness of prescribing these therapies in null/null HoFH patients. The 2023 EAS guidance recommends a short trial period in receptor defective patients, before continuing LDLR independent therapies [3]. Lomitapide lowers LDL-C independently of the LDLR pathway [5] and, consistent with previous studies [4, 5, 12, 26], LDL-C reduction was independent of the LDLR mutation status.

Lomitapide was generally well tolerated in this analysis and the main adverse events reported were transient increases in transaminases < 3x ULN in all but one case, or mild to moderate GI symptoms that were manageable with modifications in dosage or temporary dose reduction. GI tolerability was achieved with a strong emphasis by the treating physician on the importance of adhering to a low-fat diet, and patients had access to a specialised dietician, especially in the last year of treatment; this was also reflected by the mean BMI remaining stable during treatment. Lomitapide did not reduce plasma HDL-C levels and hepatic elasticity remained normal in the majority of patients.

The real-world data collected in this retrospective analysis emphasize the need for intensive use of lipid-lowering therapy to reach LDL-C goal, and also highlights the benefits of a tailored approach to treatment. Interestingly, at last follow-up, all patients were treated only with statins, ezetimibe and lomitapide, despite also having access to apheresis and PCSK9 inhibitors. Our results suggest that, in many patients with HoFH, lomitapide could be considered as the preferred adjunct to statins and ezetimibe.

Of note, half of the patients included in this analysis were not diagnosed with HoFH until well into adulthood, and it required a major cardiovascular event or procedure before the diagnosis of HoFH was made. Furthermore, some patients had not been treated at specialist centers before their first cardiovascular event, despite a family history indicative of genetically raised LDL-C and/or characteristic symptoms such as xanthomas. This highlights the need for better education around this condition to facilitate earlier diagnosis, referral to a specialist lipid clinic and prompt treatment with maximally tolerated lipid-lowering therapies.

A strength of this analysis is the long-term follow-up and detailed information collected, with patients receiving lomitapide for up to 7 years treatment. Long-term safety and effectiveness data are important, as HoFH patients require life-long intensive lipid-lowering treatments to adequately reduce LDL-C to goal levels and prevent CVD development or further progression. Limitations of this analysis included the small sample size, due to the rarity of HoFH, and the retrospective, observational design. Furthermore, as the patients were on a range of background LLTs during lomitapide treatment, the clinical effect of these therapies cannot be discounted. There was also no formal measure of adherence to lomitapide, other LLTs, or to a low-fat diet, and some patients experienced interruptions to treatment because of medication supply issues and adverse events, which could have had a bearing on the results. Finally, since this was a single-center case series, this may not be reflective of experiences in other clinical centers. Additional long-term studies with a larger patient population are required to further evaluate the cardiovascular and other outcomes in lomitapide treated patients.