Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study

Abstract

Backgroundand aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH.Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4%) patients had hypertension, one (11.1%) had diabetes mellitus, two (22.2%) were active smokers, and five (55.5%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa).Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.

Advances in Treatment of Dyslipidemia

“…During the follow-up, the reduction in LDL-C levels was consistently maintained throughout the entire 9-year study [101]. Subanalysis showed that lomitapide is not only efficacious and safe for patients with classical HoFH but also for those with ARH [102].…”

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

“…Since in case of biallelic pathogenic variants in the LDLR gene, only a very low residual activity of the LDLR is present, novel and effective therapies for HoFH are independent of the LDLR activity. These therapies include lomitapide for the inhibition of microsomal triglyceride transfer protein (MTTP), leading to a decreased production of VLDLs by the liver [ 37 , 38 ] or monoclonal antibodies for the inhibition of the Angiopoietin-Like Protein 3 (ANGPTL3), which was proved to increase IDL and LDL clearance by LDLR independent pathways [ 39 ]. Bempedoic acid is another drug acting independently of LDLR used in HeFH patients; it is an inhibitor of the ATP citrate lyase, the enzyme transforming citrate into acetyl-CoA molecules used for fatty acid synthesis [ 40 ].…”