INTRODUCTION
Homozygous familial hypercholesterolemia (HoFH) is an autosomal semidominant disease characterized by markedly high levels of low-density lipoprotein cholesterol (LDL-C) leading to an increased risk for premature atherosclerotic cardiovascular disease (ASCVD), high burden of CV outcomes and early mortality [1, 2]. It is caused by pathogenic variants in the LDL receptor (LDLR) gene or other genes affecting LDLR function [3]. HoFH affects approximately 1 in 160,000 to 360,000 individuals worldwide [4,5]. Despite its significant health implications, underdiagnosis and undertreatment remain major challenges in managing this condition. Current estimates suggest that approximately 30,000 people globally have HoFH; however, less than 5% of these are properly identified and treated [4, 5]. Genetic alterations in HoFH that result in minimal or absent LDL receptor (LDLR) expression (null homozygotes) lead to significantly higher LDL-C levels compared to alterations that only partially reduce LDLR expression, such as having two non-null alleles or one null and one non-null allele (non-null homozygotes) [6]. This distinction is crucial, as HoFH accelerates the onset of ASCVD, with individuals carrying null-null LDLR variants at a higher risk of premature ASCVD. Untreated patients with HoFH typically do not survive beyond the third decade, underscoring the importance of early intervention to optimally manage LDL-C and to lower the risk of CV events [7, 8].
Combination of lipid-lowering therapy (LLT), including different available therapies and lipoprotein apheresis (LA), is the cornerstone management of HoFH, alongside lifestyle modifications [1]. Guidelines recommend early initiation of multiple LLTs such as high-intensity statins, ezetimibe, PCSK9 inhibitors (evolocumab or alirocumab), angiopoietin-like 3 (ANGPTL3) inhibitors such as evinacumab and mipomersen, and lomitapide [1, 7, 9, 10, 11]. Statins and PCSK9 inhibitors, which upregulate hepatic LDL receptors, reduce LDL-C by LDLR alleles [1, 12, 13]. Lomitapide, acting independently of LDLR, is an alternative but carries some safety concerns including gastrointestinal issues and hepatic steatosis [14, 15]. Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipid metabolism, primarily inhibiting lipoprotein lipase (LPL) and endothelial lipase. Evinacumab, an ANGPTL3 monoclonal antibody, has proved effective in patients aged ≥12 years, in reducing LDL-C by ~50% in the ELIPSE HoFH trial when used alongside maximally tolerated LLTs and/or lipoprotein apheresis [16, 17]. The purpose of this meta-analysis was to evaluate and compare the efficacy and safety of PCSK9 and ANGPTL3 inhibitors in the treatment of HoFH.