Breakthrough LDL-C reduction in a patient with autosomal recessive homozygous familial hypercholesterolemia: Efficacy of evinacumab after LDL-apheresis discontinuation.

BACKGROUND: Autosomal recessive homozygous familial hypercholesterolemia (AR-HoFH) is a severe lipid disorder leading to early-onset atherosclerotic cardiovascular disease (ASCVD) due to extreme low-density lipoprotein cholesterol (LDL-C) elevations. Despite high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, many patients require LDL-apheresis for LDL-C control.

CASE REPORT: We present the case of a male in his late fifties diagnosed with AR-HoFH, confirmed by genetic testing revealing biallelic pathogenic LDLRAP1 variations (NM_015627.2: c.928_930del/p.Gln310del, homozygous). The patient showed extreme hypercholesterolemia with an LDL-C exceeding 500 mg/dL (12.9 mmol/L) at diagnosis, despite high-intensity statins. At 39 years of age, he suffered a myocardial infarction with multivessel coronary artery disease requiring percutaneous coronary intervention. Despite escalation to rosuvastatin 40 mg daily, ezetimibe 10 mg daily, and alirocumab 150 mg every 2 weeks, LDL-C levels remained persistently elevated. In 2023, recurrent angina prompted coronary angiography, revealing in-stent restenosis in the right coronary artery (RCA) and a new critical stenosis in the left anterior descending (LAD) artery, requiring further revascularization. Given persistently high LDL-C levels averaging 171 mg/dL prior to apheresis despite maximal lipid-lowering therapy, biweekly LDL-apheresis was initiated and continued for 1 year. In December 2024, evinacumab (15 mg/kg intravenous monthly) was introduced following regulatory approval. Over the first 3 months, average LDL-C was reduced to 79.6 mg/dL, representing a 53.5% reduction compared to the mean preapheresis baseline, and permitting discontinuation of apheresis after the final session on January 3, 2025. By March 2025, LDL-C remained stable at 62 mg/dL (1.6 mmol/L), approaching but not fully meeting the <55 mg/dL LDL-C target recommended for secondary prevention according to current European guidelines. The patient tolerated evinacumab well, with comprehensive biochemical monitoring showing no hepatic, renal, or hematologic abnormalities. Although reintroduction of LDL-apheresis remains a potential strategy, lomitapide could also be considered in combination with evinacumab to enhance LDL-C lowering. However, its use in our setting is currently limited by economic constraints.

CONCLUSION: The introduction of evinacumab, an LDL receptor-independent lipid-lowering therapy, achieved robust and sustained LDL-C reduction, while eliminating the need for LDL-apheresis and reducing the indirect logistical burden of frequent hospital-based treatments in this patient with AR-HoFH.